Liver

24 December 2020

14:11

Wilson's disease

Wilson's disease is an autosomal recessive disorder characterised by excessive copper deposition in the tissues. Metabolic abnormalities include increased copper absorption from the small intestine and decreased hepatic copper excretion. Wilson's disease is caused by a defect in the ATP7B gene located on chromosome 13.

The onset of symptoms is usually between 10 - 25 years. Children usually present with liver disease whereas the first sign of disease in young adults is often neurological disease

Features result from excessive copper deposition in the tissues, especially the brain, liver and cornea:

· liver: hepatitis, cirrhosis

· neurological:

o basal ganglia degeneration: in the brain, most copper is deposited in the basal ganglia, particularly in the putamen and globus pallidus

o speech, behavioural and psychiatric problems are often the first manifestations

o also: asterixis, chorea, dementia, parkinsonism

· Kayser-Fleischer rings

o green-brown rings in the periphery of the iris

o due to copper accumulation in Descemet membrane

o present in around 50% of patients with isolated hepatic Wilson's disease and 90% who have neurological involvement

· renal tubular acidosis (esp. Fanconi syndrome)

· haemolysis

· blue nails

Diagnosis

· slit lamp examination for Kayser-Fleischer rings

· reduced serum caeruloplasmin

· reduced total serum copper (counter-intuitive, but 95% of plasma copper is carried by ceruloplasmin)

o free (non-ceruloplasmin-bound) serum copper is increased

· increased 24hr urinary copper excretion

Management

· penicillamine (chelates copper) has been the traditional first-line treatment

· trientine hydrochloride is an alternative chelating agent which may become first-line treatment in the future

· tetrathiomolybdate is a newer agent that is currently under investigation

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:12

Primary sclerosing cholangitis

Primary sclerosing cholangitis is a biliary disease of unknown aetiology characterised by inflammation and fibrosis of intra and extra-hepatic bile ducts.

Associations

· ulcerative colitis: 4% of patients with UC have PSC, 80% of patients with PSC have UC

· Crohn's (much less common association than UC)

· HIV

Features

· cholestasis

o jaundice, pruritus

o raised bilirubin + ALP

· right upper quadrant pain

· fatigue

Investigation

· endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP) are the standard diagnostic investigations, showing multiple biliary strictures giving a 'beaded' appearance

· p-ANCA may be positive

· there is a limited role for liver biopsy, which may show fibrous, obliterative cholangitis often described as 'onion skin'

Complications

· cholangiocarcinoma (in 10%)

· increased risk of colorectal cancer

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:12

Variceal haemorrhage

Acute treatment of variceal haemorrhage

· ABC: patients should ideally be resuscitated prior to endoscopy

· correct clotting: FFP, vitamin K

· vasoactive agents:

o terlipressin is currently the only licensed vasoactive agent and is supported by NICE guidelines. It has been shown to be of benefit in initial haemostasis and preventing rebleeding

o octreotide may also be used although there is some evidence that terlipressin has a greater effect on reducing mortality

· prophylactic antibiotics have been shown to reduce mortality in patients with liver cirrhosis. Quinolones are typically used. NICE support this in their 2016 guidelines: 'Offer prophylactic intravenous antibiotics for people with cirrhosis who have upper gastrointestinal bleeding.'

· endoscopy: endoscopic variceal band ligation is superior to endoscopic sclerotherapy. NICE recommend band ligation

· Sengstaken-Blakemore tube if uncontrolled haemorrhage

· Transjugular Intrahepatic Portosystemic Shunt (TIPSS) if above measures fail

o connects the hepatic vein to the portal vein

o exacerbation of hepatic encephalopathy is a common complication

Prophylaxis of variceal haemorrhage

· propranolol: reduced rebleeding and mortality compared to placebo

· endoscopic variceal band ligation (EVL) is superior to endoscopic sclerotherapy. It should be performed at two-weekly intervals until all varices have been eradicated. Proton pump inhibitor cover is given to prevent EVL-induced ulceration. This is supported by NICE who recommend: 'Offer endoscopic variceal band ligation for the primary prevention of bleeding for people with cirrhosis who have medium to large oesophageal varices.'

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:12

Ischaemia to the lower gastrointestinal tract

Ischaemia to the lower gastrointestinal tract can result in a variety of clinical conditions. Whilst there is no standard classification it can be useful to separate cases into 3 main conditions

· acute mesenteric ischaemia

· chronic mesenteric ischaemia

· ischaemic colitis

Venn diagram showing types of bowel ischaemia

Common features in bowel ischaemia

Common predisposing factors

· increasing age

· atrial fibrillation - particularly for mesenteric ischaemia

· other causes of emboli: endocarditis, malignancy

· cardiovascular disease risk factors: smoking, hypertension, diabetes

· cocaine: ischaemic colitis is sometimes seen in young patients following cocaine use

Common features

· abdominal pain - in acute mesenteric ischaemia this is often of sudden onset, severe and out-of-keeping with physical exam findings

· rectal bleeding

· diarrhoea

· fever

· bloods typically show an elevated white blood cell count associated with a lactic acidosis

Diagnosis

· CT is the investigation of choice

Acute mesenteric ischaemia

Acute mesenteric ischaemia is typically caused by an embolism resulting in occlusion of an artery which supplies the small bowel, for example the superior mesenteric artery. Classically patients have a history of atrial fibrillation.

The abdominal pain is typically severe, of sudden onset and out-of-keeping with physical exam findings.

Management

· urgent surgery is usually required

· poor prognosis, especially if surgery delayed

Chronic mesenteric ischaemia

Chronic mesenteric ischaemia is a relatively rare clinical diagnosis due to it's non-specific features and may be thought of as 'intestinal angina'. Colickly, intermittent abdominal pain occurs.

Ischaemiac colitis

Ischaemic colitis describes an acute but transient compromise in the blood flow to the large bowel. This may lead to inflammation, ulceration and haemorrhage. It is more likely to occur in 'watershed' areas such as the splenic flexure that are located at the borders of the territory supplied by the superior and inferior mesenteric arteries.

Investigations

· 'thumbprinting' may be seen on abdominal x-ray due to mucosal oedema/haemorrhage

Management

- usually supportive

- surgery may be required in a minority of cases if conservative measures fail. Indications would include generalised peritonitis, perforation or ongoing haemorrhage

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:12

Alcoholic liver disease

Alcoholic liver disease covers a spectrum of conditions:

· alcoholic fatty liver disease

· alcoholic hepatitis

· cirrhosis

Selected investigation findings:

· gamma-GT is characteristically elevated

· the ratio of AST:ALT is normally > 2, a ratio of > 3 is strongly suggestive of acute alcoholic hepatitis

Selected management notes for alcoholic hepatitis:

· glucocorticoids (e.g. prednisolone) are often used during acute episodes of alcoholic hepatitis

o Maddrey's discriminant function (DF) is often used during acute episodes to determine who would benefit from glucocorticoid therapy

o it is calculated by a formula using prothrombin time and bilirubin concentration

· pentoxyphylline is also sometimes used

o the STOPAH study (see reference) compared the two common treatments for alcoholic hepatitis, pentoxyphylline and prednisolone. It showed that prednisolone improved survival at 28 days and that pentoxyphylline did not improve outcomes

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:12

Dysphagia

The table below gives characteristic exam question features for conditions causing dysphagia. Remember that new-onset dysphagia is a red flag symptom that requires urgent endoscopy, regardless of age or other symptoms.

Causes	Notes
Oesophageal cancer	Dysphagia may be associated with weight loss, anorexia or vomiting during eating Past history may include Barrett's oesophagus, GORD, excessive smoking or alcohol use
Oesophagitis	There may be a history of heartburn Odynophagia but no weight loss and systemically well
Oesophageal candidiasis	There may be a history of HIV or other risk factors such as steroid inhaler use
Achalasia	Dysphagia of both liquids and solids from the start Heartburn Regurgitation of food - may lead to cough, aspiration pneumonia etc
Pharyngeal pouch	More common in older men Represents a posteromedial herniation between thyropharyngeus and cricopharyngeus muscles Usually not seen but if large then a midline lump in the neck that gurgles on palpation Typical symptoms are dysphagia, regurgitation, aspiration and chronic cough. Halitosis may occasionally be seen
Systemic sclerosis	Other features of CREST syndrome may be present, namely Calcinosis, Raynaud's phenomenon, oEsophageal dysmotility, Sclerodactyly, Telangiectasia As well as oesophageal dysmotility the lower oesophageal sphincter (LES) pressure is decreased. This contrasts to achalasia where the LES pressure is increased
Myasthenia gravis	Other symptoms may include extraocular muscle weakness or ptosis Dysphagia with liquids as well as solids
Globus hystericus	There may be a history of anxiety Symptoms are often intermittent and relieved by swallowing Usually painless - the presence of pain should warrant further investigation for organic causes

Causes of dysphagia - by classification

As with many conditions, it's often useful to think about causes of a symptom in a structured way:

Classification	Examples
Extrinsic	· Mediastinal masses · Cervical spondylosis
Oesophageal wall	· Achalasia · Diffuse oesophageal spasm · Hypertensive lower oesophageal sphincter
Intrinsic	· Tumours · Strictures · Oesophageal web · Schatzki rings
Neurological	· CVA · Parkinson's disease · Multiple Sclerosis · Brainstem pathology · Myasthenia Gravis

Investigation

All patients require an upper GI endoscopy unless there are compelling reasons for this not to be performed. Motility disorders may be best appreciated by undertaking fluoroscopic swallowing studies.

A full blood count should be performed.

Ambulatory oesophageal pH and manometry studies will be required to evaluate conditions such as achalasia and patients with GORD being considered for fundoplication surgery.

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:12

Clostridium difficile

Clostridium difficile is a Gram positive rod often encountered in hospital practice. It produces an exotoxin which causes intestinal damage leading to a syndrome called pseudomembranous colitis. Clostridium difficile develops when the normal gut flora are suppressed by broad-spectrum antibiotics. Clindamycin is historically associated with causing Clostridium difficile but the aetiology has evolved significantly over the past 10 years. Second and third generation cephalosporins are now the leading cause of Clostridium difficile.

Other than antibiotics, risk factors include:

· proton pump inhibitors

Features

· diarrhoea

· abdominal pain

· a raised white blood cell count (WCC) is characteristic

· if severe toxic megacolon may develop

The Public Health England severity scale is often used as this may determine treatment:

Mild	Moderate	Severe	life-threatening
Normal WCC	↑ WCC ( < 15 x 109/L) Typically 3-5 loose stools per day	↑ WCC ( > 15 x 109/L) or an acutely ↑ creatinine (> 50% above baseline) or a temperature > 38.5°C or evidence of severe colitis(abdominal or radiological signs)	Hypotension Partial or complete ileus Toxic megacolon, or CT evidence of severe disease

Diagnosis

· is made by detecting Clostridium difficile toxin (CDT) in the stool

· Clostridium difficile antigen positivity only shows exposure to the bacteria, rather than current infection

Management

· first-line therapy is oral metronidazole for 10-14 days

· if severe or not responding to metronidazole then oral vancomycin may be used

o recurrent infection occurs in around 20% of patients, increasing to 50% after their second episode

· fidaxomicin may also be used for patients who are not responding , particularly those with multiple co-morbidities

· for life-threatening infections a combination of oral vancomycin and intravenous metronidazole should be used

Other therapies

· bezlotoxumab is a monoclonal antibody which targets Clostridium difficile toxin B - it is not in widespread use

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:12

Ulcerative colitis: management

Treatment can be divided into inducing and maintaining remission. NICE updated their guidelines on the management of ulcerative colitis in 2019.

The severity of UC is usually classified as being mild, moderate or severe:

· mild: < 4 stools/day, only a small amount of blood

· moderate: 4-6 stools/day, varying amounts of blood, no systemic upset

· severe: >6 bloody stools per day + features of systemic upset (pyrexia, tachycardia, anaemia, raised inflammatory markers)

Inducing remission

Treating mild-to-moderate ulcerative colitis

· proctitis

o topical (rectal) aminosalicylate: for distal colitis rectal mesalazine has been shown to be superior to rectal steroids and oral aminosalicylates

o if remission is not achieved within 4 weeks, add an oral aminosalicylate

o if remission still not achieved add topical or oral corticosteroid

· proctosigmoiditis and left-sided ulcerative colitis

o topical (rectal) aminosalicylate

o if remission is not achieved within 4 weeks, add a high-dose oral aminosalicylate OR switch to a high-dose oral aminosalicylate and a topical corticosteroid

o if remission still not achieved stop topical treatments and offer an oral aminosalicylate and an oral corticosteroid

· extensive disease

o topical (rectal) aminosalicylate and a high-dose oral aminosalicylate:

o if remission is not achieved within 4 weeks, stop topical treatments and offer a high-dose oral aminosalicylate and an oral corticosteroid

Severe colitis

· should be treated in hospital

· intravenous steroids are usually given first-line

o intravenous ciclosporin may be used if steroid are contraindicated

· if after 72 hours there has been no improvement, consider adding intravenous ciclosporin to intravenous corticosteroids or consider surgery

Maintaining remission

Following a mild-to-moderate ulcerative colitis flare

· proctitis and proctosigmoiditis

o topical (rectal) aminosalicylate alone (daily or intermittent) or

o an oral aminosalicylate plus a topical (rectal) aminosalicylate (daily or intermittent) or

o an oral aminosalicylate by itself: this may not be effective as the other two options

· left-sided and extensive ulcerative colitis

o low maintenance dose of an oral aminosalicylate

Following a severe relapse or >=2 exacerbations in the past year

· oral azathioprine or oral mercaptopurine

Other points

· methotrexate is not recommended for the management of UC (in contrast to Crohn's disease)

· there is some evidence that probiotics may prevent relapse in patients with mild to moderate disease

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:13

Haemochromatosis: investigation and management

Haemochromatosis is an autosomal recessive disorder of iron absorption and metabolism resulting in iron accumulation. It is caused by inheritance of mutations in the HFE gene on both copies of chromosome 6*.

There is continued debate about the best investigation to screen for haemochromatosis.

· general population: transferrin saturation is considered the most useful marker. Ferritin should also be measured but is not usually abnormal in the early stages of iron accumulation

· testing family members: genetic testing for HFE mutation

These guidelines may change as HFE gene analysis become less expensive

Diagnostic tests

· molecular genetic testing for the C282Y and H63D mutations

· liver biopsy: Perl's stain

Typical iron study profile in patient with haemochromatosis

· transferrin saturation > 55% in men or > 50% in women

· raised ferritin (e.g. > 500 ug/l) and iron

· low TIBC

Management

· Venesection is the first-line treatment

o monitoring adequacy of venesection: transferrin saturation should be kept below 50% and the serum ferritin concentration below 50 ug/l

· desferrioxamine may be used second-line

Joint x-rays characteristically show chondrocalcinosis

*there are rare cases of families with classic features of genetic haemochromatosis but no mutation in the HFE gene

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:13

Oesophageal cancer

Until recent times oesophageal cancer was most commonly due to a squamous cell carcinoma but the incidence of adenocarcinoma is rising rapidly. Adenocarcinoma is now the most common type of oesophageal cancer and is more likely to develop in patients with a history of gastro-oesophageal reflux disease (GORD) or Barrett's.

The majority of adenocarcinomas are located near the gastroesophageal junction whereas squamous cell tumours are most commonly found in the upper two-thirds of the oesophagus.

	Adenocarcinoma	Squamous cell cancer
Epidemiology	Most common type in the UK/US	Most common type in the developing world
Location	Lower third - near the gastroesophageal junction	Upper two-thirds of the oesophagus
Risk factors	· GORD · Barrett's oesophagus · smoking · achalasia · obesity	· smoking · alcohol · achalasia · Plummer-Vinson syndrome · diets rich in nitrosamines

Features

· dysphagia: the most common presenting symptom

· anorexia and weight loss

· vomiting

· other possible features include: odynophagia, hoarseness, melaena, cough

Diagnosis

· Upper GI endoscopy is the first line test

· Contrast swallow may be of benefit in classifying benign motility disorders but has no place in the assessment of tumours

· Staging is initially undertaken with CT scanning of the chest, abdomen and pelvis. If overt metastatic disease is identified using this modality then further complex imaging is unnecessary

· If CT does not show metastatic disease, then local stage may be more accurately assessed by use of endoscopic ultrasound

· Staging laparoscopy is performed to detect occult peritoneal disease. PET CT is performed in those with negative laparoscopy. Thoracoscopy is not routinely performed.

Treatment

· Operable disease is best managed by surgical resection.

· The most standard procedure is an Ivor- Lewis type oesophagectomy. This procedure involves the mobilisation of the stomach and division of the oesophageal hiatus. The abdomen is closed and a right-sided thoracotomy performed. The stomach is brought into the chest and the oesophagus mobilised further. An intrathoracic oesophagogastric anastomosis is constructed. Alternative surgical strategies include a transhiatal resection (for distal lesions), a left thoracoabdominal resection (difficult access due to thoracic aorta) and a total oesophagectomy (McKeown) with a cervical oesophagogastric anastomosis.

· The biggest surgical challenge is that of anastomotic leak, with an intrathoracic anastomosis this will result in mediastinitis. With high mortality. The McKeown technique has an intrinsically lower systemic insult in the event of anastomotic leakage.

· In addition to surgical resection many patients will be treated with adjuvant chemotherapy.

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:13

Pancreatic cancer

Pancreatic cancer is often diagnosed late as it tends to present in a non-specific way. Over 80% of pancreatic tumours are adenocarcinomas which typically occur at the head of the pancreas.

Associations

· increasing age

· smoking

· diabetes

· chronic pancreatitis (alcohol does not appear an independent risk factor though)

· hereditary non-polyposis colorectal carcinoma

· multiple endocrine neoplasia

· BRCA2 gene

· KRAS gene mutation

Features

· classically painless jaundice

o pale stools, dark urine, and pruritus

o cholestatic liver function tests

· Courvoisier's law states that in the presence of painless obstructive jaundice, a palpable gallbladder is unlikely to be due to gallstones

· however, patients typically present in a non-specific way with anorexia, weight loss, epigastric pain

· loss of exocrine function (e.g. steatorrhoea)

· loss of endocrine function (e.g. diabetes mellitus)

· atypical back pain is often seen

· migratory thrombophlebitis (Trousseau sign) is more common than with other cancers

Investigation

· ultrasound has a sensitivity of around 60-90%

· high-resolution CT scanning is the investigation of choice if the diagnosis is suspected

· imaging may demonstrate the 'double duct' sign - the presence of simultaneous dilatation of the common bile and pancreatic ducts

Management

· less than 20% are suitable for surgery at diagnosis

· a Whipple's resection (pancreaticoduodenectomy) is performed for resectable lesions in the head of pancreas. Side-effects of a Whipple's include dumping syndrome and peptic ulcer disease

· adjuvant chemotherapy is usually given following surgery

· ERCP with stenting is often used for palliation

© Image used on license from Radiopaedia

ERCP showing invasive ductal adenocarcinoma. Note the dilation of the common bile duct due to the pancreatic lesion

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:13

Acute upper gastrointestinal bleeding

NICE published guidelines in 2012 on the management of acute upper gastrointestinal bleeding which is most commonly due to either peptic ulcer disease or oesophageal varices. Some of the key points are detailed below.

Risk assessment

· use the Blatchford score at first assessment, and

· the full Rockall score after endoscopy

Blatchford score

Admission risk marker	Score
Urea (mmol/l)	6·5 - 8 = 2 8 - 10 = 3 10 - 25 = 4 > 25 = 6
Haemoglobin (g/l)	Men · 12 - 13 = 1 · 10 - 12 = 3 · < 10 = 6 Women · 10 - 12 = 1 · < 10 = 6
Systolic blood pressure (mmHg)	100 - 109 = 1 90 - 99 = 2 < 90 = 3
Other markers	Pulse >=100/min = 1 Presentation with melaena = 1 Presentation with syncope = 2 Hepatic disease = 2 Cardiac failure = 2

Patients with a Blatchford score of 0 may be considered for early discharge.

Resuscitation

· ABC, wide-bore intravenous access * 2

· platelet transfusion if actively bleeding platelet count of less than 50 x 10*9/litre

· fresh frozen plasma to patients who have either a fibrinogen level of less than 1 g/litre, or a prothrombin time (international normalised ratio) or activated partial thromboplastin time greater than 1.5 times normal

· prothrombin complex concentrate to patients who are taking warfarin and actively bleeding

Endoscopy

· should be offered immediately after resuscitation in patients with a severe bleed

· all patients should have endoscopy within 24 hours

Management of non-variceal bleeding

· NICE do not recommend the use of proton pump inhibitors (PPIs) before endoscopy to patients with suspected non-variceal upper gastrointestinal bleeding although PPIs should be given to patients with non-variceal upper gastrointestinal bleeding and stigmata of recent haemorrhage shown at endoscopy

· if further bleeding then options include repeat endoscopy, interventional radiology and surgery

Management of variceal bleeding

· terlipressin and prophylactic antibiotics should be given to patients at presentation (i.e. before endoscopy)

· band ligation should be used for oesophageal varices and injections of N-butyl-2-cyanoacrylate for patients with gastric varices

· transjugular intrahepatic portosystemic shunts (TIPS) should be offered if bleeding from varices is not controlled with the above measures

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:13

Carcinoid tumours

Carcinoid syndrome

· usually occurs when metastases are present in the liver and release serotonin into the systemic circulation

· may also occur with lung carcinoid as mediators are not 'cleared' by the liver

Features

· flushing (often earliest symptom)

· diarrhoea

· bronchospasm

· hypotension

· right heart valvular stenosis (left heart can be affected in bronchial carcinoid)

· other molecules such as ACTH and GHRH may also be secreted resulting in, for example, Cushing's syndrome

· pellagra can rarely develop as dietary tryptophan is diverted to serotonin by the tumour

Investigation

· urinary 5-HIAA

· plasma chromogranin A y

Management

· somatostatin analogues e.g. octreotide

· diarrhoea: cyproheptadine may help

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:13

Hepatitis B serology

Interpreting hepatitis B serology is a dying art form which still occurs at regular intervals in medical exams. It is important to remember a few key facts:

· surface antigen (HBsAg) is the first marker to appear and causes the production of anti-HBs

· HBsAg normally implies acute disease (present for 1-6 months)

· if HBsAg is present for > 6 months then this implies chronic disease (i.e. Infective)

· Anti-HBs implies immunity (either exposure or immunisation). It is negative in chronic disease

· Anti-HBc implies previous (or current) infection. IgM anti-HBc appears during acute or recent hepatitis B infection and is present for about 6 months. IgG anti-HBc persists

· HbeAg results from breakdown of core antigen from infected liver cells as is, therefore, a marker of infectivity

Example results

· previous immunisation: anti-HBs positive, all others negative

· previous hepatitis B (> 6 months ago), not a carrier: anti-HBc positive, HBsAg negative

· previous hepatitis B, now a carrier: anti-HBc positive, HBsAg positive

HBsAg = ongoing infection, either acute or chronic if present > 6 months

anti-HBc = caught, i.e. negative if immunized

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:13

Primary biliary cholangitis

Primary biliary cholangitis (previously referred to as primary biliary cirrhosis) is a chronic liver disorder typically seen in middle-aged females (female:male ratio of 9:1). The aetiology is not fully understood although it is thought to be an autoimmune condition. Interlobular bile ducts become damaged by a chronic inflammatory process causing progressive cholestasis which may eventually progress to cirrhosis. The classic presentation is itching in a middle-aged woman

Associations

· Sjogren's syndrome (seen in up to 80% of patients)

· rheumatoid arthritis

· systemic sclerosis

· thyroid disease

Clinical features

· early: may be asymptomatic (e.g. raised ALP on routine LFTs) or fatigue, pruritus

· cholestatic jaundice

· hyperpigmentation, especially over pressure points

· around 10% of patients have right upper quadrant pain

· xanthelasmas, xanthomata

· also: clubbing, hepatosplenomegaly

· late: may progress to liver failure

Diagnosis

· anti-mitochondrial antibodies (AMA) M2 subtype are present in 98% of patients and are highly specific

· smooth muscle antibodies in 30% of patients

· raised serum IgM

Management

· first-line: ursodeoxycholic acid

o slows disease progression and improves symptoms

· pruritus: cholestyramine

· fat-soluble vitamin supplementation

· liver transplantation

o e.g. if bilirubin > 100 (PBC is a major indication)

o recurrence in graft can occur but is not usually a problem

Complications

· cirrhosis → portal hypertension → ascites, variceal haemorrhage

· osteomalacia and osteoporosis

· significantly increased risk of hepatocellular carcinoma (20-fold increased risk)

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:13

Autoimmune hepatitis

Autoimmune hepatitis is condition of unknown aetiology which is most commonly seen in young females. Recognised associations include other autoimmune disorders, hypergammaglobulinaemia and HLA B8, DR3. Three types of autoimmune hepatitis have been characterised according to the types of circulating antibodies present

Type I	Type II	Type III
Anti-nuclear antibodies (ANA) and/or anti-smooth muscle antibodies (SMA) Affects both adults and children	Anti-liver/kidney microsomal type 1 antibodies (LKM1) Affects children only	Soluble liver-kidney antigen Affects adults in middle-age

Features

· may present with signs of chronic liver disease

· acute hepatitis: fever, jaundice etc (only 25% present in this way)

· amenorrhoea (common)

· ANA/SMA/LKM1 antibodies, raised IgG levels

· liver biopsy: inflammation extending beyond limiting plate 'piecemeal necrosis', bridging necrosis

Management

· steroids, other immunosuppressants e.g. azathioprine

· liver transplantation

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:13

Coeliac disease: investigation

Coeliac disease is caused by sensitivity to the protein gluten. Repeated exposure leads to villous atrophy which in turn causes malabsorption. Conditions associated with coeliac disease include dermatitis herpetiformis (a vesicular, pruritic skin eruption) and autoimmune disorders (type 1 diabetes mellitus and autoimmune hepatitis).

Diagnosis is made by a combination of immunology and jejunal biopsy. Villous atrophy and immunology normally reverses on a gluten-free diet.

NICE issued guidelines on the investigation of coeliac disease in 2009. If patients are already taking a gluten-free diet they should be asked, if possible, to reintroduce gluten for at least 6 weeks prior to testing.

Immunology

· tissue transglutaminase (TTG) antibodies (IgA) are first-choice according to NICE

· endomyseal antibody (IgA)

o needed to look for selective IgA deficiency, which would give a false negative coeliac result

· anti-gliadin antibody (IgA or IgG) tests are not recommended by NICE

· anti-casein antibodies are also found in some patients

Duodenal biopsy*

· villous atrophy

· crypt hyperplasia

· increase in intraepithelial lymphocytes

· lamina propria infiltration with lymphocytes

Rectal gluten challenge has been described but is not widely used

© Image used on license from PathoPic

Duodenal biopsy from a patient with coeliac disease. Complete atrophy of the villi with flat mucosa and marked crypt hyperplasia. Intraepithelial lymphocytosis. Dense mixed inflammatory infiltrate in the lamina propria.

© Image used on license from PathoPic

Duodenal biopsy from a patient with coeliac disease. Flat mucosa with hyperplastic crypts and dense cellular infiltrate in the lamina propria. Increased number of intraepithelial lymphocytes and vacuolated superficial epithelial cell vacuolated superficial epithelial cells. Higher magnification image on the right.

*these are also occasionally performed from the jejunum

From <https://www.passmedicine.com/review/textbook.php?s=#>

Target cells and Howell-Jolly bodies may be seen in coeliac disease → hyposplenism

From <https://www.passmedicine.com/question/questions.php?q=0>

24 December 2020

14:13

Non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is now the most common cause of liver disease in the developed world. It is largely caused by obesity and describes a spectrum of disease ranging from:

· steatosis - fat in the liver

· steatohepatitis - fat with inflammation, non-alcoholic steatohepatitis (NASH), see below

· progressive disease may cause fibrosis and liver cirrhosis

NAFLD is thought to represent the hepatic manifestation of the metabolic syndrome and hence insulin resistance is thought to be the key mechanism leading to steatosis.

Non-alcoholic steatohepatitis (NASH) is a term used to describe liver changes similar to those seen in alcoholic hepatitis in the absence of a history of alcohol abuse. It is relatively common and thought to affect around 3-4% of the general population. The progression of disease in patients with NASH may be responsible for a proportion of patients previously labelled as cryptogenic cirrhosis.

Associated factors

· obesity

· type 2 diabetes mellitus

· hyperlipidaemia

· jejunoileal bypass

· sudden weight loss/starvation

Features

· usually asymptomatic

· hepatomegaly

· ALT is typically greater than AST

· increased echogenicity on ultrasound

NICE produced guidelines on the investigation and management of NAFLD in 2016. Key points:

· there is no evidence to support screening for NAFLD in adults, even in at risk groups (e.g. type 2 diabetes)

· the guidelines are therefore based on the management of the incidental finding of NAFLD - typically asymptomatic fatty changes on liver ultrasound

· in these patients, NICE recommends the use of the enhanced liver fibrosis (ELF) blood test to check for advanced fibrosis

· the ELF blood test is a combination of hyaluronic acid + procollagen III + tissue inhibitor of metalloproteinase 1. An algorithm based on these values results in an ELF blood test score, similar to triple testing for Down's syndrome

An excellent review by Byrne et Al1 in 2018 reviewed the diagnosis and monitoring of NAFLD. It made the following suggestions if the ELF blood test was not available:

· non-invasive tests may be used to assess the severity of fibrosis

· these include the FIB4 score or NALFD fibrosis score

· these scores may be used in combination with a FibroScan (liver stiffness measurement assessed with transient elastography)

· this combination has been shown to have excellent accuracy in predicting fibrosis

Patients who are likely to have advanced fibrosis should be referred to a liver specialist. They will then likely have a liver biopsy to stage the disease more accurately.

Management

· the mainstay of treatment is lifestyle changes (particularly weight loss) and monitoring

· there is ongoing research into the role of gastric banding and insulin-sensitising drugs (e.g. metformin, pioglitazone)

References

1. BMJ 2018;362:k2734

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:13

Achalasia

Failure of oesophageal peristalsis and of relaxation of the lower oesophageal sphincter (LOS) due to degenerative loss of ganglia from Auerbach's plexus i.e. LOS contracted, oesophagus above dilated. Achalasia typically presents in middle-age and is equally common in men and women.

Clinical features

· dysphagia of BOTH liquids and solids

· typically variation in severity of symptoms

· heartburn

· regurgitation of food

o may lead to cough, aspiration pneumonia etc

· malignant change in small number of patients

Investigations

· oesophageal manometry

o excessive LOS tone which doesn't relax on swallowing

o considered the most important diagnostic test

· barium swallow

o shows grossly expanded oesophagus, fluid level

o 'bird's beak' appearance

· chest x-ray

o wide mediastinum

o fluid level

Treatment

· pneumatic (balloon) dilation is increasingly the preferred first-line option

o less invasive and quicker recovery time than surgery

o patients should be a low surgical risk as surgery may be required if complications occur

· surgical intervention with a Heller cardiomyotomy should be considered if recurrent or persistent symptoms

· intra-sphincteric injection of botulinum toxin is sometimes used in patients who are a high surgical risk

· drug therapy (e.g. nitrates, calcium channel blockers) has a role but is limited by side-effects

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:13

Alcohol: units

In 2016 the Chief Medical Officer proposed new guidelines in relation to the safe consumption of alcohol following an expert group report. The most significant change has been a reduction in the number of units it is recommending men do not exceed from 21 to 14, in line with the recommendations for women.

The government now recommend the following:

· men and women should drink no more than 14 units of alcohol per week

· they advise 'if you do drink as much as 14 units per week, it is best to spread this evenly over 3 days or more'

· pregnant women should not drink. The wording of the official advice is 'If you are pregnant or planning a pregnancy, the safest approach is not to drink alcohol at all, to keep risks to your baby to a minimum. Drinking in pregnancy can lead to long-term harm to the baby, with the more you drink the greater the risk.'

One unit of alcohol is equal to 10 mL of pure ethanol. The 'strength' of an alcoholic drink is determined by the 'alcohol by volume' (ABV).

Examples of one unit of alcohol:

· 25ml single measure of spirits (ABV 40%)

· a third of a pint of beer (ABV 5 to 6%)

· half a 175ml 'standard' glass of red wine (ABV 12%)

To calculate the number of units in a drink multiply the number of millilitres by the ABV and divide by 1,000. For example:

· half a 175ml 'standard' glass of red wine = 87.5 * 12 / 1000 = 1.05 units

· one bottle of wine = 750 * 12 / 1000 = 9 units

· one pint of 5% beer or lager = 568 * 5 / 1000 = 2.8 units

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:13

Ascites

The causes of ascites can be grouped into those with a serum-ascites albumin gradient (SAAG) <11 g/L or a gradient >11g/L as per the table below:

SAAG > 11g/L	SAAG <11g/L
Indicates portal hypertension Cirrhosis Alcoholic hepatitis Cardiac ascites Mixed ascites Massive liver metastases Fulminant hepatic failure Budd-Chiari syndrome Portal vein thrombosis Veno-occlusive disease Myxoedema Fatty liver of pregnancy	Peritoneal carcinomatosis Tuberculous peritonitis Pancreatic ascites Bowel obstruction Biliary ascites Postoperative lymphatic leak Serositis in connective tissue diseases

Management

· reducing dietary sodium

· fluid restriction is sometimes recommended if the sodium is < 125 mmol/L

· aldosterone antagonists: e.g. spironolactone

o loop diuretics are often added. Some authorities only add loop diuretics in patients who don't respond to aldosterone agonists whereas other authorities suggest starting both types of diuretic on the first presentation of ascites

· drainage if tense ascites (therapeutic abdominal paracentesis)

o large-volume paracentesis for the treatment of ascites requires albumin 'cover'. Evidence suggests this reduces paracentesis-induced circulatory dysfunction and mortality

o paracentesis induced circulatory dysfunction can occur due to large volume paracentesis (> 5 litres). It is associated with a high rate of ascites recurrence, development of hepatorenal syndrome, dilutional hyponatraemia, and high mortality rate

· prophylactic antibiotics to reduce the risk of spontaneous bacterial peritonitis. NICE recommend: 'Offer prophylactic oral ciprofloxacin or norfloxacin for people with cirrhosis and ascites with an ascitic protein of 15 g/litre or less, until the ascites has resolved'

· a transjugular intrahepatic portosystemic shunt (TIPS) may be considered in some patients

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:13

Diarrhoea

The table below gives characteristic features for conditions causing diarrhoea:

World Health Organisation definitions

· Diarrhoea: > 3 loose or watery stool per day

· Acute diarrhoea < 14 days

· Chronic diarrhoea > 14 days

Usually acute

Condition	Notes
Gastroenteritis	May be accompanied by abdominal pain or nausea/vomiting
Diverticulitis	Classically causes left lower quadrant pain, diarrhoea and fever
Antibiotic therapy	More common with broad spectrum antibiotics Clostridium difficile is also seen with antibiotic use
Constipation causing overflow	A history of alternating diarrhoea and constipation may be given May lead to faecal incontinence in the elderly

Usually chronic

Condition	Notes
Irritable bowel syndrome	Extremely common. The most consistent features are abdominal pain, bloating and change in bowel habit. Patients may be divided into those with diarrhoea predominant IBS and those with constipation-predominant IBS. Features such as lethargy, nausea, backache and bladder symptoms may also be present
Ulcerative colitis	Bloody diarrhoea may be seen. Crampy abdominal pain and weight loss are also common. Faecal urgency and tenesmus may be seen
Crohn's disease	Crampy abdominal pains and diarrhoea. Bloody diarrhoea less common than in ulcerative colitis. Other features include malabsorption, mouth ulcers, perianal disease and intestinal obstruction
Colorectal cancer	Symptoms depend on the site of the lesion but include diarrhoea, rectal bleeding, anaemia and constitutional symptoms e.g. Weight loss and anorexia
Coeliac disease	In children may present with failure to thrive, diarrhoea and abdominal distension In adults lethargy, anaemia, diarrhoea and weight loss are seen. Other autoimmune conditions may coexist

Other conditions associated with diarrhoea include:

· thyrotoxicosis

· laxative abuse

· appendicitis

· radiation enteritis

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:13

Dyspepsia

The 2015 NICE guidelines 'Suspected cancer: recognition and referral' further updated the advice on who needs urgent referral for an endoscopy (i.e. within 2 weeks). The list below combines the advice for oesophageal and stomach cancer, with the bold added by the author, not NICE.

Urgent

All patients who've got dysphagia

All patients who've got an upper abdominal mass consistent with stomach cancer

Patients aged >= 55 years who've got weight loss, AND any of the following:

· upper abdominal pain

· reflux

· dyspepsia

Non-urgent

Patients with haematemesis

Patients aged >= 55 years who've got:

· treatment-resistant dyspepsia or

· upper abdominal pain with low haemoglobin levels or

· raised platelet count with any of the following: nausea, vomiting, weight loss, reflux, dyspepsia, upper abdominal pain

· nausea or vomiting with any of the following: weight loss, reflux, dyspepsia, upper abdominal pain

Managing patients who do not meet referral criteria ('undiagnosed dyspepsia')

This can be summarised at a step-wise approach

· 1. Review medications for possible causes of dyspepsia

· 2. Lifestyle advice

· 3. Trial of full-dose proton pump inhibitor for one month OR a 'test and treat' approach for H. pylori

o if symptoms persist after either of the above approaches then the alternative approach should be tried

Testing for H. pylori infection

· initial diagnosis: NICE recommend using a carbon-13 urea breath test or a stool antigen test, or laboratory-based serology 'where its performance has been locally validated'

· test of cure:

o there is no need to check for H. pylori eradication if symptoms have resolved following test and treat

o however, if repeat testing is required then a carbon-13 urea breath test should be used

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:13

Gallstones

Up to 24% of women and 12% of men may have gallstones. Of these up to 30% may develop local infection and cholecystitis. In patients subjected to surgery, 12% will have stones contained within the common bile duct. The majority of gallstones are of a mixed composition (50%) with pure cholesterol stones accounting for 20% of cases.

The aetiology of CBD stones differs in the world, in the West most CBD stones are the result of migration. In the East, a far higher proportion arise in the CBD de novo.

The classical symptoms are of colicky right upper quadrant pain that occurs postprandially. The symptoms are usually worst following a fatty meal when cholecystokinin levels are highest and gallbladder contraction is maximal.

Investigation

In almost all suspected cases the standard diagnostic workup consists of abdominal ultrasound and liver function tests. Of patients who have stones within the bile duct, 60% will have at least one abnormal result on LFT's. Ultrasound is an important test, but is operator dependent and therefore may occasionally need to be repeated if a negative result is at odds with the clinical picture. Where stones are suspected in the bile duct the options lie between magnetic resonance cholangiography and intraoperative imaging. The choice between these two options is determined by the skills and experience of the surgeon. The advantages of intraoperative imaging are less useful in making therapeutic decisions if the operator is unhappy about proceeding the bile duct exploration, and in such circumstances, preoperative MRCP is probably a better option.

Specific gallstone and gallbladder related disease

Disease	Features	Management
Biliary colic	Colicky abdominal pain, worse postprandially, worse after fatty foods	If imaging shows gallstones and history compatible then laparoscopic cholecystectomy
Acute cholecystitis	Right upper quadrant pain Fever Murphys sign on examination Occasionally mildly deranged LFT's (especially if Mirizzi syndrome)	Imaging (USS) and cholecystectomy (ideally within 48 hours of presentation) (2)
Gallbladder abscess	Usually prodromal illness and right upper quadrant pain Swinging pyrexia Patient may be systemically unwell Generalised peritonism not present	Imaging with USS +/- CT Scanning Ideally, surgery although subtotal cholecystectomy may be needed if Calot's triangle is hostile In unfit patients, percutaneous drainage may be considered
Cholangitis	Patient severely septic and unwell Jaundice Right upper quadrant pain	Fluid resuscitation Broad-spectrum intravenous antibiotics Correct any coagulopathy Early ERCP
Gallstone ileus	Patients may have a history of previous cholecystitis and known gallstones Small bowel obstruction (may be intermittent)	Laparotomy and removal of the gallstone from small bowel, the enterotomy must be made proximal to the site of obstruction and not at the site of obstruction. The fistula between the gallbladder and duodenum should not be interfered with.
Acalculous cholecystitis	Patients with intercurrent illness (e.g. diabetes, organ failure) Patient of systemically unwell Gallbladder inflammation in absence of stones High fever	If patient fit then cholecystectomy, if unfit then percutaneous cholecystostomy

Treatment

Asymptomatic gallstones which are located in the gallbladder are common and do not require treatment. However, if stones are present in the common bile duct there is an increased risk of complications such as cholangitis or pancreatitis and surgical management should be considered.

Patients with asymptomatic gallstones rarely develop symptoms related to them (less than 2% per year) and may, therefore, be managed expectantly. In almost all cases of symptomatic gallstones the treatment of choice is cholecystectomy performed via the laparoscopic route. In the very frail patient, there is sometimes a role for the selective use of ultrasound guided cholecystostomy.

During the course of the procedure, some surgeons will routinely perform either intraoperative cholangiography to either confirm anatomy or to exclude CBD stones. The latter may be more easily achieved by use of laparoscopic ultrasound. If stones are found then the options lie between early ERCP in the day or so following surgery or immediate surgical exploration of the bile duct. When performed via the trans cystic route this adds little in the way of morbidity and certainly results in faster recovery. Where transcystic exploration fails the alternative strategy is that of formal choledochotomy. The exploration of a small duct is challenging and ducts of less than 8mm should not be explored. Small stones that measure less than 5mm may be safely left and most will pass spontaneously.

Risks of ERCP(1)

· Bleeding 0.9% (rises to 1.5% if sphincterotomy performed)

· Duodenal perforation 0.4%

· Cholangitis 1.1%

· Pancreatitis 1.5%

References

1. Williams E et al. Guidelines on the management of common bile duct stones (CBDS)Gut 2008;57:10041021

2. Gurusamy KS, Samraj K. Early versus delayed laparoscopic cholecystectomy for acute cholecystitis. Cochrane Database Syst Rev. 2006 Oct 18;(4):CD005440.

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:13

Hepatobiliary disease and related disorders

The table below gives characteristic exam question features for conditions causing hepatobiliary disease and related disorders:

Condition	Features
Viral hepatitis	Common symptoms include: · nausea and vomiting, anorexia · myalgia · lethargy · right upper quadrant (RUQ) pain Questions may point to risk factors such as foreign travel or intravenous drug use.
Congestive hepatomegaly	The liver only usually causes pain if stretched. One common way this can occur is as a consequence of congestive heart failure. In severe cases cirrhosis may occur.
Biliary colic	RUQ pain, intermittent, usually begins abruptly and subsides gradually. Attacks often occur after eating. Nausea is common. It is sometimes taught that patients are female, forties, fat and fair although this is obviously a generalisation.
Acute cholecystitis	Pain similar to biliary colic but more severe and persistent. The pain may radiate to the back or right shoulder. The patient may be pyrexial and Murphy's sign positive (arrest of inspiration on palpation of the RUQ)
Ascending cholangitis	An infection of the bile ducts commonly secondary to gallstones. Classically presents with a triad of: · fever (rigors are common) · RUQ pain · jaundice
Gallstone ileus	This describes small bowel obstruction secondary to an impacted gallstone. It may develop if a fistula forms between a gangrenous gallbladder and the duodenum. Abdominal pain, distension and vomiting are seen.
Cholangiocarcinoma	Persistent biliary colic symptoms, associated with anorexia, jaundice and weight loss. A palpable mass in the right upper quadrant (Courvoisier sign), periumbilical lymphadenopathy (Sister Mary Joseph nodes) and left supraclavicular adenopathy (Virchow node) may be seen
Acute pancreatitis	Usually due to alcohol or gallstones Severe epigastric pain Vomiting is common Examination may reveal tenderness, ileus and low-grade fever Periumbilical discolouration (Cullen's sign) and flank discolouration (Grey-Turner's sign) is described but rare
Pancreatic cancer	Painless jaundice is the classical presentation of pancreatic cancer. However pain is actually a relatively common presenting symptom of pancreatic cancer. Anorexia and weight loss are common
Amoebic liver abscess	Typical symptoms are malaise, anorexia and weight loss. The associated RUQ pain tends to be mild and jaundice is uncommon.

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:13

Spontaneous bacterial peritonitis

Spontaneous bacterial peritonitis (SBP) is a form of peritonitis usually seen in patients with ascites secondary to liver cirrhosis.

Features

· ascites

· abdominal pain

· fever

Diagnosis

· paracentesis: neutrophil count > 250 cells/ul

· the most common organism found on ascitic fluid culture is E. coli

Management

· intravenous cefotaxime is usually given

Antibiotic prophylaxis should be given to patients with ascites if:

· patients who have had an episode of SBP

· patients with fluid protein <15 g/l and either Child-Pugh score of at least 9 or hepatorenal syndrome

· NICE recommend: 'Offer prophylactic oral ciprofloxacin or norfloxacin for people with cirrhosis and ascites with an ascitic protein of 15 g/litre or less until the ascites has resolved'

Alcoholic liver disease is a marker of poor prognosis in SBP.

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:13

Ulcerative colitis

Ulcerative colitis (UC) is a form of inflammatory bowel disease. Inflammation always starts at rectum (hence it is the most common site for UC), never spreads beyond ileocaecal valve and is continuous. The peak incidence of ulcerative colitis is in people aged 15-25 years and in those aged 55-65 years.

The initial presentation is usually following insidious and intermittent symptoms. Features include:

· bloody diarrhoea

· urgency

· tenesmus

· abdominal pain, particularly in the left lower quadrant

· extra-intestinal features (see below)

Questions regarding the 'extra-intestinal' features of inflammatory bowel disease are common:

	Common to both Crohn's disease (CD) and Ulcerative colitis (UC)	Notes
Related to disease activity	Arthritis: pauciarticular, asymmetric Erythema nodosum Episcleritis Osteoporosis	Arthritis is the most common extra-intestinal feature in both CD and UC Episcleritis is more common in CD
Unrelated to disease activity	Arthritis: polyarticular, symmetric Uveitis Pyoderma gangrenosum Clubbing Primary sclerosing cholangitis	Primary sclerosing cholangitis is much more common in UC Uveitis is more common in UC

Venn diagram showing shared features and differences between ulcerative colitis and Crohn's disease. Note that whilst some features are present in both, some are much more common in one of the conditions, for example colorectal cancer in ulcerative colitis

Pathology

· red, raw mucosa, bleeds easily

· no inflammation beyond submucosa (unless fulminant disease)

· widespread ulceration with preservation of adjacent mucosa which has the appearance of polyps ('pseudopolyps')

· inflammatory cell infiltrate in lamina propria

· neutrophils migrate through the walls of glands to form crypt abscesses

· depletion of goblet cells and mucin from gland epithelium

· granulomas are infrequent

Barium enema

· loss of haustrations

· superficial ulceration, 'pseudopolyps'

· long standing disease: colon is narrow and short -'drainpipe colon'

© Image used on license from Radiopaedia

Abdominal x-ray from a patient with ulcerative colitis showing lead pipe appearance of the colon (red arrows). Ankylosis of the left sacroiliac joint and partial ankylosis on the right (yellow arrow), reinforcing the link with sacroilitis.

© Image used on license from Radiopaedia

Barium enema from a patient with ulcerative colitis. The whole colon, without skips is affected by an irregular mucosa with loss of normal haustral markings.

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:13

Helicobacter pylori: tests

Urea breath test

· patients consume a drink containing carbon isotope 13 (13C) enriched urea

· urea is broken down by H. pylori urease

· after 30 mins patient exhale into a glass tube

· mass spectrometry analysis calculates the amount of 13C CO2

· should not be performed within 4 weeks of treatment with an antibacterial or within 2 weeks of an antisecretory drug (e.g. a proton pump inhibitor)

· sensitivity 95-98%, specificity 97-98%

· may be used to check for H. pylori eradication

Rapid urease test (e.g. CLO test)

· biopsy sample is mixed with urea and pH indicator

· colour change if H pylori urease activity

· sensitivity 90-95%, specificity 95-98%

Serum antibody

· remains positive after eradication

· sensitivity 85%, specificity 80%

Culture of gastric biopsy

· provide information on antibiotic sensitivity

· sensitivity 70%, specificity 100%

Gastric biopsy

· histological evaluation alone, no culture

· sensitivity 95-99%, specificity 95-99%

Stool antigen test

· sensitivity 90%, specificity 95%

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:13

Acute liver failure

Acute liver failure describes the rapid onset of hepatocellular dysfunction leading to a variety of systemic complications.

Causes

· paracetamol overdose

· alcohol

· viral hepatitis (usually A or B)

· acute fatty liver of pregnancy

Features*

· jaundice

· coagulopathy: raised prothrombin time

· hypoalbuminaemia

· hepatic encephalopathy

· renal failure is common ('hepatorenal syndrome')

*remember that 'liver function tests' do not always accurately reflect the synthetic function of the liver. This is best assessed by looking at the prothrombin time and albumin level.

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:13

Budd-Chiari syndrome

Budd-Chiari syndrome, or hepatic vein thrombosis, is usually seen in the context of underlying haematological disease or another procoagulant condition.

Causes

· polycythaemia rubra vera

· thrombophilia: activated protein C resistance, antithrombin III deficiency, protein C & S deficiencies

· pregnancy

· combined oral contraceptive pill: accounts for around 20% of cases

The features are classically a triad of:

· abdominal pain: sudden onset, severe

· ascites → abdominal distension

· tender hepatomegaly

Investigations

· ultrasound with Doppler flow studies is very sensitive and should be the initial radiological investigation

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:13

Coeliac disease

Coeliac disease is an autoimmune condition caused by sensitivity to the protein gluten. It is thought to affect around 1% of the UK population. Repeated exposure leads to villous atrophy which in turn causes malabsorption. Conditions associated with coeliac disease include dermatitis herpetiformis (a vesicular, pruritic skin eruption) and autoimmune disorders (type 1 diabetes mellitus and autoimmune hepatitis). It is strongly associated with HLA-DQ2 (95% of patients) and HLA-DQ8 (80%).

In 2009 NICE issued guidelines on the investigation of coeliac disease. They suggest that the following patients should be screened for coeliac disease:

Signs and symptoms	Conditions
· Chronic or intermittent diarrhoea · Failure to thrive or faltering growth (in children) · Persistent or unexplained gastrointestinal symptoms including nausea and vomiting · Prolonged fatigue ('tired all the time') · Recurrent abdominal pain, cramping or distension · Sudden or unexpected weight loss · Unexplained iron-deficiency anaemia, or other unspecified anaemia	· Autoimmune thyroid disease · Dermatitis herpetiformis · Irritable bowel syndrome · Type 1 diabetes · First-degree relatives (parents, siblings or children) with coeliac disease

Complications

· anaemia: iron, folate and vitamin B12 deficiency (folate deficiency is more common than vitamin B12 deficiency in coeliac disease)

· hyposplenism

· osteoporosis, osteomalacia

· lactose intolerance

· enteropathy-associated T-cell lymphoma of small intestine

· subfertility, unfavourable pregnancy outcomes

· rare: oesophageal cancer, other malignancies

© Image used on license from PathoPic

Duodenal biopsy from a patient with coeliac disease. Complete atrophy of the villi with flat mucosa and marked crypt hyperplasia. Intraepithelial lymphocytosis. Dense mixed inflammatory infiltrate in the lamina propria.

© Image used on license from PathoPic

Duodenal biopsy from a patient with coeliac disease. Flat mucosa with hyperplastic crypts and dense cellular infiltrate in the lamina propria. Increased number of intraepithelial lymphocytes and vacuolated superficial epithelial cell vacuolated superficial epithelial cells. Higher magnification image on the right.

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:13

Coeliac disease: management

The management of coeliac disease involves a gluten-free diet. Gluten-containing cereals include:

· wheat: bread, pasta, pastry

· barley: beer

o whisky is made using malted barley. Proteins such as gluten are however removed during the distillation process making it safe to drink for patients with coeliac disease

· rye

· oats

o some patients with coeliac disease appear able to tolerate oats

Some notable foods which are gluten-free include:

· rice

· potatoes

· corn (maize)

Tissue transglutaminase antibodies may be checked to check compliance with a gluten-free diet.

Immunisation

· Patients with coeliac disease often have a degree of functional hyposplenism

· For this reason, all patients with coeliac disease are offered the pneumococcal vaccine

o Coeliac UK recommends that everyone with coeliac disease is vaccinated against pneumococcal infection and has a booster every 5 years

· Currrent guidelines suggest giving the influenza vaccine on an individual basis.

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:14

Colorectal cancer: genetics

It is currently thought there are three types of colon cancer:

· sporadic (95%)

· hereditary non-polyposis colorectal carcinoma (HNPCC, 5%)

· familial adenomatous polyposis (FAP, <1%)

Studies have shown that sporadic colon cancer may be due to a series of genetic mutations. For example, more than half of colon cancers show allelic loss of the APC gene. It is believed a further series of gene abnormalities e.g. activation of the K-ras oncogene, deletion of p53 and DCC tumour suppressor genes lead to invasive carcinoma

HNPCC, an autosomal dominant condition, is the most common form of inherited colon cancer. Around 90% of patients develop cancers, often of the proximal colon, which are usually poorly differentiated and highly aggressive. Currently seven mutations have been identified, which affect genes involved in DNA mismatch repair leading to microsatellite instability. The most common genes involved are:

· MSH2 (60% of cases)

· MLH1 (30%)

Patients with HNPCC are also at a higher risk of other cancers, with endometrial cancer being the next most common association, after colon cancer.

The Amsterdam criteria are sometimes used to aid diagnosis:

· at least 3 family members with colon cancer

· the cases span at least two generations

· at least one case diagnosed before the age of 50 years

FAP is a rare autosomal dominant condition which leads to the formation of hundreds of polyps by the age of 30-40 years. Patients inevitably develop carcinoma. It is due to a mutation in a tumour suppressor gene called adenomatous polyposis coli gene (APC), located on chromosome 5. Genetic testing can be done by analysing DNA from a patient's white blood cells. Patients generally have a total colectomy with ileo-anal pouch formation in their twenties.

Patients with FAP are also at risk from duodenal tumours. A variant of FAP called Gardner's syndrome can also feature osteomas of the skull and mandible, retinal pigmentation, thyroid carcinoma and epidermoid cysts on the skin

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:14

Crohn's disease: management

Crohn's disease is a form of inflammatory bowel disease. It commonly affects the terminal ileum and colon but may be seen anywhere from the mouth to anus. NICE published guidelines on the management of Crohn's disease in 2012.

General points

· patients should be strongly advised to stop smoking

· some studies suggest an increased risk of relapse secondary to NSAIDs and the combined oral contraceptive pill but the evidence is patchy

Inducing remission

· glucocorticoids (oral, topical or intravenous) are generally used to induce remission. Budesonide is an alternative in a subgroup of patients

· enteral feeding with an elemental diet may be used in addition to or instead of other measures to induce remission, particularly if there is concern regarding the side-effects of steroids (for example in young children)

· 5-ASA drugs (e.g. mesalazine) are used second-line to glucocorticoids but are not as effective

· azathioprine or mercaptopurine* may be used as an add-on medication to induce remission but is not used as monotherapy. Methotrexate is an alternative to azathioprine

· infliximab is useful in refractory disease and fistulating Crohn's. Patients typically continue on azathioprine or methotrexate

· metronidazole is often used for isolated peri-anal disease

Maintaining remission

· as above, stopping smoking is a priority (remember: smoking makes Crohn's worse, but may help ulcerative colitis)

· azathioprine or mercaptopurine is used first-line to maintain remission

· methotrexate is used second-line

· 5-ASA drugs (e.g. mesalazine) should be considered if a patient has had previous surgery

Surgery

· around 80% of patients with Crohn's disease will eventually have surgery

· see below for further detail

Surgical interventions in Crohn's disease

The commonest disease pattern in Crohn's is stricturing terminal ileal disease and this often culminates in an ileocaecal resection. Other procedures performed include segmental small bowel resections and stricturoplasty. Colonic involvement in patients with Crohn's is not common and, where found, distribution is often segmental. However, despite this distribution segmental resections of the colon in patients with Crohn's disease are generally not advocated because the recurrence rate in the remaining colon is extremely high, as a result, the standard options of colonic surgery in Crohn's patients are generally; sub total colectomy, panproctocolectomy and staged sub total colectomy and proctectomy. Restorative procedures such as ileoanal pouch have no role in therapy.

Crohn's disease is notorious for the developmental of intestinal fistulae; these may form between the rectum and skin (perianal) or the small bowel and skin. Fistulation between loops of bowel may also occur and result in bacterial overgrowth and malabsorption. Management of enterocutaneous fistulae involves controlling sepsis, optimising nutrition, imaging the disease and planning definitive surgical management.

Complications of Crohn's disease

As well as the well-documented complications described above, patients are also at risk of:

· small bowel cancer (standard incidence ratio = 40)

· colorectal cancer (standard incidence ration = 2, i.e. less than the risk associated with ulcerative colitis)

· osteoporosis

*assess thiopurine methyltransferase (TPMT) activity before offering azathioprine or mercaptopurine

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:14

Hepatic encephalopathy

Hepatic encephalopathy may be seen in liver disease of any cause. The aetiology is not fully understood but is thought to include excess absorption of ammonia and glutamine from bacterial breakdown of proteins in the gut.

Whilst hepatic encephalopathy is often associated with acute liver failure it may also be seen with chronic disease. It is now recognised that many patients with liver cirrhosis may develop subtle symptoms such as mild cognitive impairment before the features become more recognisable ('minimal' or 'covert' hepatic encephalopathy). It has also been noted that transjugular intrahepatic portosystemic shunting (TIPSS) may precipitate encephalopathy.

Features

· confusion, altered GCS (see below)

· asterix: 'liver flap', arrhythmic negative myoclonus with a frequency of 3-5 Hz

· constructional apraxia: inability to draw a 5-pointed star

· triphasic slow waves on EEG

· raised ammonia level (not commonly measured anymore)

Grading of hepatic encephalopathy

· Grade I: Irritability

· Grade II: Confusion, inappropriate behaviour

· Grade III: Incoherent, restless

· Grade IV: Coma

Precipitating factors

· infection e.g. spontaneous bacterial peritonitis

· GI bleed

· post transjugular intrahepatic portosystemic shunt

· constipation

· drugs: sedatives, diuretics

· hypokalaemia

· renal failure

· increased dietary protein (uncommon)

Management

· treat any underlying precipitating cause

· NICE recommend lactulose first-line, with the addition of rifaximin for the secondary prophylaxis of hepatic encephalopathy

· lactulose is thought to work by promoting the excretion of ammonia and increasing the metabolism of ammonia by gut bacteria

· antibiotics such as rifaximin are thought to modulate the gut flora resulting in decreased ammonia production

· other options include embolisation of portosystemic shunts and liver transplantation in selected patients

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:14

Hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third most common cause of cancer worldwide. Chronic hepatitis B is the most common cause of HCC worldwide with chronic hepatitis C being the most common cause in Europe.

The main risk factor for developing HCC is liver cirrhosis, for example secondary* to hepatitis B & C, alcohol, haemochromatosis and primary biliary cirrhosis. Other risk factors include:

· alpha-1 antitrypsin deficiency

· hereditary tyrosinosis

· glycogen storage disease

· aflatoxin

· drugs: oral contraceptive pill, anabolic steroids

· porphyria cutanea tarda

· male sex

· diabetes mellitus, metabolic syndrome

Features

· tends to present late

· features of liver cirrhosis or failure may be seen: jaundice, ascites, RUQ pain, hepatomegaly, pruritus, splenomegaly

· possible presentation is decompensation in a patient with chronic liver disease

· raised AFP

Screening with ultrasound (+/- alpha-fetoprotein) should be considered for high risk groups such as:

· patients liver cirrhosis secondary to hepatitis B & C or haemochromatosis

· men with liver cirrhosis secondary to alcohol

Management options

· early disease: surgical resection

· liver transplantation

· radiofrequency ablation

· transarterial chemoembolisation

· sorafenib: a multikinase inhibitor

*Wilson's disease is an exception

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:14

Inflammatory bowel disease: key differences

The two main types of inflammatory bowel disease are Crohn's disease and ulcerative colitis. They have many similarities in terms of presenting symptoms, investigation findings and management options.

Venn diagram showing shared features and differences between ulcerative colitis and Crohn's disease. Note that whilst some features are present in both, some are much more common in one of the conditions, for example colorectal cancer in ulcerative colitis

There are however some key differences which are highlighted in table below:

	Crohn's disease (CD)	Ulcerative colitis (UC)
Features	Diarrhoea usually non-bloody Weight loss more prominent Upper gastrointestinal symptoms, mouth ulcers, perianal disease Abdominal mass palpable in the right iliac fossa	Bloody diarrhoea more common Abdominal pain in the left lower quadrant Tenesmus
Extra-intestinal	Gallstones are more common secondary to reduced bile acid reabsorption Oxalate renal stones*	Primary sclerosing cholangitis more common
Complications	Obstruction, fistula, colorectal cancer	Risk of colorectal cancer high in UC than CD
Pathology	Lesions may be seen anywhere from the mouth to anus Skip lesions may be present	Inflammation always starts at rectum and never spreads beyond ileocaecal valve Continuous disease
Histology	Inflammation in all layers from mucosa to serosa · increased goblet cells · granulomas	No inflammation beyond submucosa (unless fulminant disease) - inflammatory cell infiltrate in lamina propria · neutrophils migrate through the walls of glands to form crypt abscesses · depletion of goblet cells and mucin from gland epithelium · granulomas are infrequent
Endoscopy	Deep ulcers, skip lesions - 'cobble-stone' appearance	Widespread ulceration with preservation of adjacent mucosa which has the appearance of polyps ('pseudopolyps')
Radiology	Small bowel enema · high sensitivity and specificity for examination of the terminal ileum · strictures: 'Kantor's string sign' · proximal bowel dilation · 'rose thorn' ulcers · fistulae	Barium enema · loss of haustrations · superficial ulceration, 'pseudopolyps' · long standing disease: colon is narrow and short -'drainpipe colon'

*impaired bile acid rebsorption increases the loss calcium in the bile. Calcium normally binds oxalate.

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:14

Ischaemic hepatitis

Ischaemic hepatitis is a diffuse hepatic injury resulting from acute hypoperfusion (sometimes known as 'shock liver'). It is not an inflammatory process. It is diagnosed in the presence of an inciting event (e.g. a cardiac arrest) and marked increases in aminotransferase levels (exceeding 1000 international unit/L or 50 times the upper limit of normal). Often, it will occur in conjunction with acute kidney injury (tubular necrosis) or other end-organ dysfunction.

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:14

Metoclopramide

Metoclopramide is a D2 receptor antagonist* mainly used in the management of nausea. Other uses include:

· gastro-oesophageal reflux disease

· prokinetic action is useful in gastroparesis secondary to diabetic neuropathy

· often combined with analgesics for the treatment of migraine (migraine attacks result in gastroparesis, slowing the absorption of analgesics)

Adverse effects

· extrapyramidal effects: oculogyric crisis. This is particularly a problem in children and young adults

· hyperprolactinaemia

· tardive dyskinesia

· parkinsonism

Metoclopramide should be avoided in bowel obstruction, but may be helpful in paralytic ileus.

*whilst metoclopramide is primarily a D2 receptor antagonist, the mechanism of action is quite complicated:

· it is also a mixed 5-HT3 receptor antagonist/5-HT4 receptor agonist

· the antiemetic action is due to its antagonist activity at D2 receptors in the chemoreceptor trigger zone. At higher doses the 5-HT3 receptor antagonist also has an effect

· the gastroprokinetic activity is mediated by D2 receptor antagonist activity and 5-HT4 receptor agonist activity

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:14

Peptic ulcer disease (uncomplicated)

Risk factors

· Helicobacter pylori is associated with the majority of peptic ulcers:

o 95% of duodenal ulcers

o 75% of gastric ulcers

· drugs:

o NSAIDs

o SSRIs

o corticosteroids

o bisphosphonates

· Zollinger-Ellison syndrome: rare cause characterised by excessive levels of gastrin, usually from a gastrin secreting tumour

· the role of alcohol and smoking is not clear

Features

· epigastric pain

· nausea

· duodenal ulcers

o more common than gastric ulcers

o epigastric pain when hungry, relieved by eating

· gastric ulcers

o epigastric pain worsened by eating

Investigation

· Helicobacter pylori should be tested for

o either a Urea breath test or stool antigen test should be used first-line

Management

· if Helicobacter pylori is negative then proton pump inhibitors (PPIs) should be given until the ulcer is healed

· if Helicobacter pylori is positive then eradication therapy should be given

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:14

Proton pump inhibitors

Proton pump inhibitors (PPI) cause irreversible blockade of H+/K+ ATPase of the gastric parietal cell.

Examples include omeprazole and lansoprazole.

Adverse effects

· hyponatraemia, hypomagnasaemia

· osteoporosis → increased risk of fractures

· microscopic colitis

· increased risk of Clostridium difficile infections

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:14

Ulcerative colitis: flares

Most ulcerative colitis flares occur without an identifiable trigger. However, a number of factors are often linked:

· stress

· medications

o NSAIDs

o antibiotics

· cessation of smoking

Flares of ulcerative colitis are usually classified as either mild, moderate or severe:

Mild	Moderate	Severe
Fewer than four stools daily, with or without blood No systemic disturbance Normal erythrocyte sedimentation rate and C-reactive protein values	Four to six stools a day, with minimal systemic disturbance	More than six stools a day, containing blood Evidence of systemic disturbance, e.g. · fever · tachycardia · abdominal tenderness, distension or reduced bowel sounds · anaemia · hypoalbuminaemia

Patients with evidence of severe disease should be admitted to hospital.

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:14

Acute appendicitis

Acute appendicitis is the most common acute abdominal condition requiring surgery. It can occur at any age but is most common in young people aged 10-20 years.

Abdominal pain is seen in the vast majority of patients:

· peri-umbilical abdominal pain (visceral stretching of appendix lumen and appendix is midgut structure) radiating to the right iliac fossa (RIF) due to localised parietal peritoneal inflammation.

· the migration of the pain from the centre to the RIF has been shown to be one of the strongest indicators of appendicitis

· patients often report the pain being worse on coughing or going over speed bumps. Children typically can't hop on the right leg due to the pain.

Other features:

· vomit once or twice but marked and persistent vomiting is unusual

· diarrhoea is rare. However, pelvic appendicitis may cause localised rectal irritation of some loose stools. A pelvic abscess may also cause diarrhoea

· mild pyrexia is common - temperature is usually 37.5-38oC. Higher temperatures are more typical of conditions like mesenteric adenitis

· anorexia is very common. It is very unusual for patients with appendicitis to be hungry

· around 50% of patients have the typical symptoms of anorexia, peri-umbilical pain and nausea followed by more localised right lower quadrant pain

Examination

· generalised peritonitis if perforation has occurred or localised peritonism

· retrocaecal appendicitis may have relatively few signs

· digital rectal examination may reveal boggy sensation if pelvic abscess is present, or even right-sided tenderness with a pelvic appendix

· Rovsing's sign (palpation in the LIF causes pain in the RIF) is now thought to be of limited value

Diagnosis

· typically raised inflammatory markers coupled with compatible history and examination findings should be enough to justify appendicectomy

· a neutrophil-predominant leucocytosis is seen in 80-90%

· urine analysis: useful to exclude pregnancy in women, renal colic and urinary tract infection. In patients with appendicitis, urinalysis may show mild leucocytosis but no nitrites

· ultrasound is useful in females where pelvic organ pathology is suspected. Although it is not always possible to visualise the appendix on ultrasound, the presence of free fluid (always pathological in males) should raise suspicion

· CT scans are widely used in patients with suspected appendicitis in the US but this practice has not currently reached the UK, due to the concerns regarding excessive ionising radiation and resource limitations

Management

· appendicectomy which can be performed via either an open or laparoscopic approach. Laparoscopic appendicectomy is now the treatment of choice

· administration of prophylactic intravenous antibiotics reduces wound infection rates

· patients with perforated appendicitis (typical around 15-20%) require copious abdominal lavage.

· patients without peritonitis who have an appendix mass should receive broad-spectrum antibiotics and consideration given to performing an interval appendicectomy.

· be wary in the older patients who may have either an underlying caecal malignancy or perforated sigmoid diverticular disease.

· trials have looked at the use of intravenous antibiotics alone in the treatment of appendicitis. The evidence currently suggests that whilst this is successful in the majority of patients, it is associated with a longer hospital stay and up to 20% of patients go on to have an appendicectomy within 12 months.

Image sourced from Wikipedia

Ultrasound examination may show evidence of lumenal obstruction and thickening of the appendiceal wall as shown below

Image sourced from Wikipedia

Laparoscopic appendicectomy is becoming increasing popular as demonstrated below

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:14

Alcoholic ketoacidosis

Alcoholic ketoacidosis is a non-diabetic euglycaemic form of ketoacidosis. It occurs in people who regularly drink large amounts of alcohol. Often alcoholics will not eat regularly and may vomit food that they do eat, leading to episodes of starvation. Once the person becomes malnourished, after an alcohol binge the body can start to break down body fat, producing ketones. Hence the patient develops a ketoacidosis.

It typically presents with a pattern of:

· Metabolic acidosis

· Elevated anion gap

· Elevated serum ketone levels

· Normal or low glucose concentration

The most appropriate treatment is an infusion of saline & thiamine. Thiamine is required to avoid Wernicke encephalopathy or Korsakoff psychosis.

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:14

Aminosalicylate drugs

5-aminosalicyclic acid (5-ASA) is released in the colon and is not absorbed. It acts locally as an anti-inflammatory. The mechanism of action is not fully understood but 5-ASA may inhibit prostaglandin synthesis

Sulphasalazine

· a combination of sulphapyridine (a sulphonamide) and 5-ASA

· many side-effects are due to the sulphapyridine moiety: rashes, oligospermia, headache, Heinz body anaemia, megaloblastic anaemia, lung fibrosis

· other side-effects are common to 5-ASA drugs (see mesalazine)

Mesalazine

· a delayed release form of 5-ASA

· sulphapyridine side-effects seen in patients taking sulphasalazine are avoided

· mesalazine is still however associated with side-effects such as GI upset, headache, agranulocytosis, pancreatitis*, interstitial nephritis

Olsalazine

· two molecules of 5-ASA linked by a diazo bond, which is broken by colonic bacteria

Aminosalicylates are associated with a variety of haematological adverse effects, including agranulocytosis - FBC is a key investigation in an unwell patient taking them.

*pancreatitis is 7 times more common in patients taking mesalazine than sulfasalazine

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:14

Barrett's oesophagus

Barrett's refers to the metaplasia of the lower oesophageal mucosa, with the usual squamous epithelium being replaced by columnar epithelium. There is an increased risk of oesophageal adenocarcinoma, estimated at 50-100 fold. There are no screening programs for Barrett's - it's typically identified when patients have an endoscopy for evaluation of upper gastrointestinal symptoms such as dyspepsia.

Barrett's can be subdivided into short (<3cm) and long (>3cm). The length of the affected segment correlates strongly with the chances of identifying metaplasia. The overall prevalence of Barrett's oesophagus is difficult to determine but may be in the region of 1 in 20 and is identified in up to 12% of those undergoing endoscopy for reflux.

Histological features

· the columnar epithelium may resemble that of either the cardiac region of the stomach or that of the small intestine (e.g. with goblet cells, brush border)

Risk factors

· gastro-oesophageal reflux disease (GORD) is the single strongest risk factor

· male gender (7:1 ratio)

· smoking

· central obesity

Interestingly alcohol does not seem to be an independent risk factor for Barrett's although it is associated with both GORD and oesophageal cancer.

Whilst Barrett's oesophagus itself is asymptomatic clearly patients will often have coexistent GORD symptoms.

Management

· endoscopic surveillance with biopsies

· high-dose proton pump inhibitor: whilst this is commonly used in patients with Barrett's the evidence base that this reduces the change of progression to dysplasia or induces regression of the lesion is limited

Endoscopic surveillance

· for patients with metaplasia (but not dysplasia) endoscopy is recommended every 3-5 years

If dysplasia of any grade is identified endoscopic intervention is offered. Options include:

· endoscopic mucosal resection

· radiofrequency ablation

Endoscopy image showing a short segment of Barrett's oesophagus

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:14

Crohn's disease: investigation

Crohn's disease is a form of inflammatory bowel disease. It commonly affects the terminal ileum and colon but may be seen anywhere from the mouth to anus

Bloods

· C-reactive protein correlates well with disease activity

Endoscopy

· colonoscopy is the investigation of choice

· features suggest of Crohn's include deep ulcers, skip lesions

Histology

· inflammation in all layers from mucosa to serosa

· goblet cells

· granulomas

Small bowel enema

· high sensitivity and specificity for examination of the terminal ileum

· strictures: 'Kantor's string sign'

· proximal bowel dilation

· 'rose thorn' ulcers

· fistulae

© Image used on license from Radiopaedia

Barium study is shown from a patient with worsening Crohn's disease. Long segment of narrowed terminal ileum in a 'string like' configuration in keeping with a long stricture segment. Termed 'Kantor's string sign'.

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:14

Hepatomegaly

Common causes of hepatomegaly

· Cirrhosis: if early disease, later liver decreases in size. Associated with a non-tender, firm liver

· Malignancy: metastatic spread or primary hepatoma. Associated with a hard, irregular. liver edge

· Right heart failure: firm, smooth, tender liver edge. May be pulsatile

Other causes

· viral hepatitis

· glandular fever

· malaria

· abscess: pyogenic, amoebic

· hydatid disease

· haematological malignancies

· haemochromatosis

· primary biliary cirrhosis

· sarcoidosis, amyloidosis

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:14

Liver cirrhosis

Liver cirrhosis remains a significant problem in the developed world, account for 60,000 deaths in the UK each year.

Causes:

· alcohol

· non-alcoholic fatty liver disease (NAFLD)

· viral hepatitis (B and C)

Diagnosis

· traditionally a liver biopsy was used. This procedure is however associated with adverse effects such as bleeding and pain

· other techniques such as transient elastography and acoustic radiation force impulse imaging are increasingly used and were recommended by NICE in their 2016 guidelines

· for patients with NAFLD, NICE recommend using the enhanced liver fibrosis score to screen for patients who need further testing

What is transient elastography?

· brand name 'Fibroscan'

· uses a 50-MHz wave is passed into the liver from a small transducer on the end of an ultrasound probe

· measures the 'stiffness' of the liver which is a proxy for fibrosis

In terms of screening for cirrhosis NICE made a specific recommendation, suggesting to offer transient elastography to:

· people with hepatitis C virus infection

· men who drink over 50 units of alcohol per week and women who drink over 35 units of alcohol per week and have done so for several months

· people diagnosed with alcohol-related liver disease

Further investigations

· NICE recommend doing an upper endoscopy to check for varices in patient's with a new diagnosis of cirrhosis

· liver ultrasound every 6 months (+/- alpha-feto protein) to check for hepatocellular cancer

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:14

Oesophageal disorders

The table below lists a small group of less common oesophageal disorders.

Disorder	Notes
Plummer-Vinson syndrome	Triad of: · dysphagia (secondary to oesophageal webs) · glossitis · iron-deficiency anaemia Treatment includes iron supplementation and dilation of the webs
Mallory-Weiss syndrome	Severe vomiting → painful mucosal lacerations at the gastroesophageal junction resulting in haematemesis. Common in alcoholics
Boerhaave syndrome	Severe vomiting → oesophageal rupture

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:14

Peutz-Jeghers syndrome

Peutz-Jeghers syndrome is an autosomal dominant condition characterised by numerous hamartomatous polyps in the gastrointestinal tract. It is also associated with pigmented freckles on the lips, face, palms and soles. Although the polyps themselves don't have malignant potential, around 50% of patients will have died from another gastrointestinal tract cancer by the age of 60 years.

Genetics

· autosomal dominant

· responsible gene encodes serine threonine kinase LKB1 or STK11

Features

· hamartomatous polyps in GI tract (mainly small bowel)

· pigmented lesions on lips, oral mucosa, face, palms and soles

· intestinal obstruction e.g. intussusception

· gastrointestinal bleeding

Management

· conservative unless complications develop

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:14

Pharyngeal pouch

A pharyngeal pouch is a posteromedial diverticulum through Killian's dehiscence. Killian's dehiscence is a triangular area in the wall of the pharynx between the thyropharyngeus and cricopharyngeus muscles. It is more common in older patients and is 5 times more common in men

Features

· dysphagia

· regurgitation

· aspiration

· neck swelling which gurgles on palpation

· halitosis

Management

· surgery

© Image used on license from Radiopaedia

Still image taken from a barium swallow with fluoroscopy. During swallowing an outpouching of the posterior hypopharyngeal wall is visualised at the level C5-C6, right above the upper oesophageal sphincter

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:14

Small bowel bacterial overgrowth syndrome

Small bowel bacterial overgrowth syndrome (SBBOS) is a disorder characterised by excessive amounts of bacteria in the small bowel resulting in gastrointestinal symptoms.

Risk factors for SBBOS

· neonates with congenital gastrointestinal abnormalities

· scleroderma

· diabetes mellitus

It should be noted that many of the features overlap with irritable bowel syndrome:

· chronic diarrhoea

· bloating, flatulence

· abdominal pain

Diagnosis

· hydrogen breath test

· small bowel aspiration and culture: this is used less often as invasive and results are often difficult to reproduce

· clinicians may sometimes give a course of antibiotics as a diagnostic trial

Management

· correction of underlying disorder

· antibiotic therapy: rifaximin is now the treatment of choice due to relatively low resistance. Co-amoxiclav or metronidazole are also effective in the majority of patients.

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:14

Helicobacter pylori

Helicobacter pylori is a Gram negative bacteria associated with a variety of gastrointestinal problems, principally peptic ulcer disease

Associations

· peptic ulcer disease (95% of duodenal ulcers, 75% of gastric ulcers)

· gastric cancer

· B cell lymphoma of MALT tissue (eradication of H pylori results causes regression in 80% of patients)

· atrophic gastritis

The role of H pylori in Gastro-oesophageal reflux disease (GORD) is unclear - there is currently no role in GORD for the eradication of H pylori

Management - eradication may be achieved with a 7 day course of

· a proton pump inhibitor + amoxicillin + clarithromycin, or

· a proton pump inhibitor + metronidazole + clarithromycin

H. pylori colonized on the surface of regenerative epithelium (silver stain)

From <https://www.passmedicine.com/review/textbook.php?s=#>

Since almost all Deodenal Ulcer are caused by H. pylori (HP) (in absence of NSAID therapy) there is no need to perform a CLO test.

There are many ways to make a diagnosis of HP. Non invasive tests include Urea breath test, stool for HP antigen. Invasive tests are CLO, histological examination and culture.

The Camplyobacter-like organism (CLO) test is based on the fact that mucosal biopsy specimens can be inoculated into a medium containing urea and phenol red, a dye that turns pink in a pH of 6.0 or greater.

The pH will rise above 6.0 when HP, the Campylobacter-like organism, metabolizes urea to ammonia by way of its urease activity. This test is commercially available and therefore quite inexpensive. Only one-half hour is required for diagnosis of infection, and the test has shown 98% sensitivity and 100% specificity.

In case of a gastric ulcer (GU), since only 65-70% are due to HP, it is recommended that the HP status be confirmed (preferably by a biopsy) before starting therapy. A biopsy will also help rule out malignancy (this is not usually a concern with DU).

From <https://mle.ncl.ac.uk/cases/page/15729/>

24 December 2020

14:14

Acute abdominal pain: a very basic introduction

Acute abdominal pain is one of the most common presentations encountered in clinical practice.

Causes

One of the most common ways to think about the potential causes is the location of the pain. Sometimes patients present with generalised pain but probably the most common present is pain in a particular region of the abdomen. Some conditions characteristically cause central pain before localising to a particular area. A good example is appendicitis, which typically presents with central abdominal pain before localising to the right iliac fossa.

Diagram showing stereotypical areas where particular conditions present. The diagram is not exhaustive and only lists the more common conditions seen in clinical practice. Note how pain from renal causes such as renal/ureteric colic and pyelonephritis may radiate and move from the loins towards the suprapubic area.

This approach, whilst useful, is however limited as patients commonly present with atypical findings and as mentioned previously the site of the pain can change over time.

Another way of classifying the causes of an acute abdomen, or any condition, is by using a surgical sieve:

Infective

· gastroenteritis

· appendicitis

· diverticulitis

· pyelonephritis

· cholecystitis

· cholangitis

· pelvic inflammatory disease

· hepatitis

· pneumonia

Inflammatory

· pancreatitis

· peptic ulcer disease

Vascular

· ruptured abdominal aortic aneurysm

· mesenteric ischaemia

· myocardial infarction

Traumatic

· ruptured spleen

· perforated viscus (e.g. oesophagus, stomach, bowel)

Metabolic

· renal/ureteric stone

· diabetic ketoacidosis

The tables below gives the key characteristics of common causes of abdominal pain.

Hepatobiliary problems

Condition	Typical location of pain	Notes
Biliary colic	Right upper quadrant	Caused by a gallstone getting lodged in the bile duct Classically provoked by eating a fatty meal In contrast to acute cholecystitis no fever and inflammatory markers are normal
Acute cholecystitis	Right upper quadrant	Inflammation/infection of the gallbladder secondary to impacted gallstones Murphy's sign positive (arrest of inspiration on palpation of the RUQ) Fever and raised inflammatory markers
Ascending cholangitis	Right upper quadrant	Ascending cholangitis is a bacterial infection of the biliary tree. The most common predisposing factor is gallstones. Charcot's triad of right upper quadrant pain, fever and jaundice occurs in about 20-50% of patients
Acute pancreatitis	Epigastrium, sometimes radiating through to the back	Usually due to alcohol or gallstones Pain is often very severe. Examination may reveal tenderness, ileus and low-grade fever

Upper gastrointestinal tract problems

Condition	Typical location of pain	Notes
Peptic ulcer disease	Epigastrium	There may be a history of NSAID use or alcohol excess. Duodenal ulcers: more common than gastric ulcers, epigastric pain relieved by eating Gastric ulcers: epigastric pain worsened by eating Features of upper gastrointestinal haemorrhage may be seen (haematemesis, melena etc)

Lower gastrointestinal tract problems

Condition	Typical location of pain	Notes
Appendicitis	Right iliac fossa	Pain initial in the central abdomen before localising to the right iliac fossa (RIF). Anorexia is common. Tachycardia, low-grade pyrexia, tenderness in RIF Rovsing's sign: more pain in RIF than LIF when palpating LIF
Acute diverticulitis	Left lower quadrant	Colicky pain typically in the LLQ Diarrhoea, sometimes bloody. Fever, raised inflammatory markers and white cells
Intestinal obstruction	Central	History of malignancy (intraluminal obstruction)/previous operations (adhesions) Vomiting. Not opened bowels recently 'Tinkling' bowel sounds

Urological causes

Condition	Typical location of pain	Notes
Renal colic	Loin pain radiating to the groin	Pain is often severe but intermittent. Patient's are characteristically restless. Visible or non-visible haematuria may be present
Acute pyelonephritis	Loin pain	Fever and rigors are common as is vomiting
Urinary retention	Suprapubic	Caused by obstruction to the bladder outflow. Much more common in men, who often have a history of benign prostatic hyperplasia

Gynaecological causes

Remember, all women of a reproductive age who present with abdominal pain should be considered pregnant until proven otherwise

Condition	Typical location of pain	Notes
Ectopic pregnancy	Right or left iliac fossa	Typically presents with pain and a history of amenorrhoea for the past 6-9 weeks. Vaginal bleeding may be present

Vascular causes

Condition	Typical location of pain	Notes
Ruptured abdominal aortic aneurysm	Central abdominal pain radiating to the back	Presentation may be catastrophic (e.g. Sudden collapse) or sub-acute (persistent severe central abdominal pain with developing shock) Patients may be shocked (hypotension, tachycardic) Patients may have a history of cardiovascular disease
Mesenteric ischaemia	Central abdominal pain	Patients often have a history of atrial fibrillation or other cardiovascular disease Diarrhoea, rectal bleeding may be seen A metabolic acidosis is often seen (due to 'dying' tissue)

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:14

Crohn's disease

Crohn's disease is a form of inflammatory bowel disease. It commonly affects the terminal ileum and colon but may be seen anywhere from the mouth to anus.

Pathology

· cause is unknown but there is a strong genetic susceptibility

· inflammation occurs in all layers, down to the serosa. This is why patients with Crohn's are prone to strictures, fistulas and adhesions

Crohn's disease typically presents in late adolescence or early adulthood. Features include:

· presentation may be non-specific symptoms such as weight loss and lethargy

· diarrhoea: the most prominent symptom in adults. Crohn's colitis may cause bloody diarrhoea

· abdominal pain: the most prominent symptom in children

· perianal disease: e.g. Skin tags or ulcers

· extra-intestinal features are more common in patients with colitis or perianal disease

Investigations

· raised inflammatory markers

· increased faecal calprotectin

· anaemia

· low vitamin B12 and vitamin D

Questions regarding the 'extra-intestinal' features of inflammatory bowel disease are common:

	Common to both Crohn's disease (CD) and Ulcerative colitis (UC)	Notes
Related to disease activity	Arthritis: pauciarticular, asymmetric Erythema nodosum Episcleritis Osteoporosis	Arthritis is the most common extra-intestinal feature in both CD and UC Episcleritis is more common in CD
Unrelated to disease activity	Arthritis: polyarticular, symmetric Uveitis Pyoderma gangrenosum Clubbing Primary sclerosing cholangitis	Primary sclerosing cholangitis is much more common in UC Uveitis is more common in UC

Venn diagram showing shared features and differences between ulcerative colitis and Crohn's disease. Note that whilst some features are present in both, some are much more common in one of the conditions, for example colorectal cancer in ulcerative colitis

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:14

Drug-induced liver disease

Drug-induced liver disease is generally divided into hepatocellular, cholestatic or mixed. There is however considerable overlap, with some drugs causing a range of changes to the liver

The following drugs tend to cause a hepatocellular picture:

· paracetamol

· sodium valproate, phenytoin

· MAOIs

· halothane

· anti-tuberculosis: isoniazid, rifampicin, pyrazinamide

· statins

· alcohol

· amiodarone

· methyldopa

· nitrofurantoin

The following drugs tend to cause cholestasis (+/- hepatitis):

· combined oral contraceptive pill

· antibiotics: flucloxacillin, co-amoxiclav, erythromycin*

· anabolic steroids, testosterones

· phenothiazines: chlorpromazine, prochlorperazine

· sulphonylureas

· fibrates

· rare reported causes: nifedipine

Liver cirrhosis

· methotrexate

· methyldopa

· amiodarone

*risk may be reduced with erythromycin stearate

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:15

Ferritin

Ferritin is an intracellular protein that binds iron and stores it to be released in a controlled fashion at sites where iron is required.

Increased ferritin levels

This is typically defined as > 300 µg/L in men/postmenopausal women and > 200 µµg/L in premenopausal women.

Ferritin is an acute phase protein and may be synthesised in increased quantities in situations where inflammatory activity is ongoing. Falsely elevated results may therefore be encountered clinically and need to be taken in the context of the clinical picture and blood results.

We can split the causes of increased ferritin levels into 2 distinct categories;

Without iron overload (around 90% of patients)	With iron overload (around 10% of patients)
Inflammation (due to ferritin being an acute phase reactant) Alcohol excess Liver disease Chronic kidney disease Malignancy	Primary iron overload (hereditary haemochromatosis) Secondary iron overload (e.g. following repeated transfusions)

The best test to see whether iron overload is present is transferrin saturation. Typically, normal values of < 45% in females and < 50% in males exclude iron overload.

Reduced ferritin levels

Because iron and ferritin are bound the total body ferritin levels may be decreased in cases of iron deficiency anaemia.

Measurement of serum ferritin levels can be useful in determining whether an apparently low haemoglobin and microcytosis is truly caused by an iron deficiency state.

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:15

Gastric cancer

There are 700,000 new cases of gastric cancer worldwide each year.

Epidemiology

· overall incidence is decreasing, but incidence of tumours arising from the cardia is increasing

· peak age = 70-80 years

· more common in Japan, China, Finland and Colombia than the West

· more common in males, 2:1

Histology

· signet ring cells may be seen in gastric cancer. They contain a large vacuole of mucin which displaces the nucleus to one side. Higher numbers of signet ring cells are associated with a worse prognosis

Associations

· H. pylori infection

· blood group A: gAstric cAncer

· gastric adenomatous polyps

· pernicious anaemia

· smoking

· diet: salty, spicy, nitrates

· may be negatively associated with duodenal ulcer

Features

· dyspepsia

· nausea and vomiting

· anorexia and weight loss

· dysphagia

Investigation

· diagnosis: endoscopy with biopsy

· staging: CT or endoscopic ultrasound - endoscopic ultrasound has recently been shown to be superior to CT

Surgical aspects

There is some evidence of support a stepwise progression of the disease through intestinal metaplasia progressing to atrophic gastritis and subsequent dysplasia, through to cancer. The favoured staging system is TNM. The risk of lymph node involvement is related to size and depth of invasion; early cancers confined to submucosa have a 20% incidence of lymph node metastasis. Tumours of the gastro-oesophageal junction are classified as below:

Type 1	True oesophageal cancers and may be associated with Barrett's oesophagus.
Type 2	Carcinoma of the cardia, arising from cardiac type epithelium or short segments with intestinal metaplasia at the oesophagogastric junction.
Type 3	Sub cardial cancers that spread across the junction. Involve similar nodal stations to gastric cancer.

Image sourced from Wikipedia

Upper GI endoscopy performed for dyspepsia. The addition of dye spraying (as shown in the bottom right) may facilitate identification of smaller tumours

Staging

· CT scanning of the chest abdomen and pelvis is the routine first line staging investigation in most centres.

· Laparoscopy to identify occult peritoneal disease

· PET CT (particularly for junctional tumours)

Treatment

· Proximally sited disease greater than 5-10cm from the OG junction may be treated by sub total gastrectomy

· Total gastrectomy if tumour is <5cm from OG junction

· For type 2 junctional tumours (extending into oesophagus) oesophagogastrectomy is usual

· Endoscopic sub mucosal resection may play a role in early gastric cancer confined to the mucosa and perhaps the sub mucosa (this is debated)

· Lymphadenectomy should be performed. A D2 lymphadenectomy is widely advocated by the Japanese, the survival advantages of extended lymphadenectomy have been debated. However, the overall recommendation is that a D2 nodal dissection be undertaken.

· Most patients will receive chemotherapy either pre or post operatively.

Prognosis

UK Data

Disease extent	Percentage 5 year survival
All RO resections	54%
Early gastric cancer	91%
Stage 1	87%
Stage 2	65%
Stage 3	18%

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:15

Gilbert's syndrome

Gilbert's syndrome is an autosomal recessive* condition of defective bilirubin conjugation due to a deficiency of UDP glucuronosyltransferase. The prevalence is approximately 1-2% in the general population.

Features

· unconjugated hyperbilirubinaemia (i.e. not in urine)

· jaundice may only be seen during an intercurrent illness, exercise or fasting

Investigation and management

· investigation: rise in bilirubin following prolonged fasting or IV nicotinic acid

· no treatment required

*the exact mode of inheritance is still a matter of debate

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:15

Haemochromatosis: features

Haemochromatosis is an autosomal recessive disorder of iron absorption and metabolism resulting in iron accumulation. It is caused by inheritance of mutations in the HFE gene on both copies of chromosome 6*. It is often asymptomatic in early disease and initial symptoms often non-specific e.g. lethargy and arthralgia

Epidemiology

· 1 in 10 people of European descent carry a mutation in the genes affecting iron metabolism, mainly HFE

· prevalence in people of European descent = 1 in 200, making it more common than cystic fibrosis

Presenting features

· early symptoms include fatigue, erectile dysfunction and arthralgia (often of the hands)

· 'bronze' skin pigmentation

· diabetes mellitus

· liver: stigmata of chronic liver disease, hepatomegaly, cirrhosis, hepatocellular deposition)

· cardiac failure (2nd to dilated cardiomyopathy)

· hypogonadism (2nd to cirrhosis and pituitary dysfunction - hypogonadotrophic hypogonadism)

· arthritis (especially of the hands)

Questions have previously been asked regarding which features are reversible with treatment:

Reversible complications	Irreversible complications
· Cardiomyopathy · Skin pigmentation	· Liver cirrhosis** · Diabetes mellitus · Hypogonadotrophic hypogonadism · Arthropathy

*there are rare cases of families with classic features of genetic haemochromatosis but no mutation in the HFE gene

**whilst elevated liver function tests and hepatomegaly may be reversible, cirrhosis is not

From <https://www.passmedicine.com/review/textbook.php?s=#>

Commonly C282Y or H63D mutations HFE gene

MRI liver heart

Iron studies >50% transferrin sats

Venesection aim <100 ferritin

Refer to liver/endochronology

24 December 2020

14:15

Hepatorenal syndrome: management

The management of hepatorenal syndrome (HRS) is notoriously difficult. The ideal treatment is liver transplantation but patients are often too unwell to have surgery and there is a shortage of donors

The most accepted theory regarding the pathophysiology of HRS is that vasoactive mediators cause splanchnic vasodilation which in turn reduces the systemic vascular resistance. This results in 'underfilling' of the kidneys. This is sensed by the juxtaglomerular apparatus which then activates the renin-angiotensin-aldosterone system, causing renal vasoconstriction which is not enough to counterbalance the effects of the splanchnic vasodilation.

Hepatorenal syndrome has been categorized into two types:

Type 1 HRS	Type 2 HRS
Rapidly progressive Doubling of serum creatinine to > 221 µmol/L or a halving of the creatinine clearance to less than 20 ml/min over a period of less than 2 weeks Very poor prognosis	Slowly progressive Prognosis poor, but patients may live for longer

Management options

· vasopressin analogues, for example terlipressin, have a growing evidence base supporting their use. They work by causing vasoconstriction of the splanchnic circulation

· volume expansion with 20% albumin

· transjugular intrahepatic portosystemic shunt

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:15

Irritable bowel syndrome: management

The management of irritable bowel syndrome (IBS) is often difficult and varies considerably between patients. NICE updated it's guidelines in 2015.

First-line pharmacological treatment - according to predominant symptom

· pain: antispasmodic agents

· constipation: laxatives but avoid lactulose

· diarrhoea: loperamide is first-line

For patients with constipation who are not responding to conventional laxatives linaclotide may be considered, if:

· optimal or maximum tolerated doses of previous laxatives from different classes have not helped and

· they have had constipation for at least 12 months

Second-line pharmacological treatment

· low-dose tricyclic antidepressants (e.g. amitriptyline 5-10 mg) are used in preference to selective serotonin reuptake inhibitors

Other management options

· psychological interventions - if symptoms do not respond to pharmacological treatments after 12 months and who develop a continuing symptom profile (refractory IBS), consider referring for cognitive behavioural therapy, hypnotherapy or psychological therapy

· complementary and alternative medicines: 'do not encourage use of acupuncture or reflexology for the treatment of IBS'

General dietary advice

· have regular meals and take time to eat

· avoid missing meals or leaving long gaps between eating

· drink at least 8 cups of fluid per day, especially water or other non-caffeinated drinks such as herbal teas

· restrict tea and coffee to 3 cups per day

· reduce intake of alcohol and fizzy drinks

· consider limiting intake of high-fibre food (for example, wholemeal or high-fibre flour and breads, cereals high in bran, and whole grains such as brown rice)

· reduce intake of 'resistant starch' often found in processed foods

· limit fresh fruit to 3 portions per day

· for diarrhoea, avoid sorbitol

· for wind and bloating consider increasing intake of oats (for example, oat-based breakfast cereal or porridge) and linseeds (up to one tablespoon per day).

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:15

Malnutrition

Malnutrition is an important consequence of and contributor to chronic disease. It is clearly a complex and multifactorial problem that can be difficult to manage but there are a number of key points to remember for the exam.

NICE define malnutrition as the following:

· a Body Mass Index (BMI) of less than 18.5; or

· unintentional weight loss greater than 10% within the last 3-6 months; or

· a BMI of less than 20 and unintentional weight loss greater than 5% within the last 3-6 months

Around 10% of patients aged over 65 years are malnourished, the vast majority of those living independently, i.e. not in hospital or care/nursing homes.

Screening for malnutrition if mostly done using MUST (Malnutrition Universal Screen Tool). A link is provided to a copy of the MUST score algorithm.

· it should be done on admission to care/nursing homes and hospital, or if there is concern. For example an elderly, thin patient with pressure sores

· it takes into account BMI, recent weight change and the presence of acute disease

· categorises patients into low, medium and high risk

Management of malnutrition is difficult. NICE recommend the following points:

· dietician support if the patient is high-risk

· a 'food-first' approach with clear instructions (e.g. 'add full-fat cream to mashed potato'), rather than just prescribing oral nutritional supplements (ONS) such as Ensure

· if ONS are used they should be taken between meals, rather than instead of meals

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:15

Melanosis coli

Melanosis coli is a disorder of pigmentation of the bowel wall. Histology demonstrates pigment-laden macrophages

It is associated with laxative abuse, especially anthraquinone compounds such as senna

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:15

Pyogenic liver abscess

The most common organisms found in pyogenic liver abscesses are Staphylococcus aureus in children and Escherichia coli in adults.

Management

· drainage (typically percutaneous) and antibiotics

· amoxicillin + ciprofloxacin + metronidazole

· if penicillin allergic: ciprofloxacin + clindamycin

© Image used on license from Radiopaedia

CT showing a pyogenic liver abscess in the right lobe of the liver.

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:15

Refeeding syndrome

Refeeding syndrome describes the metabolic abnormalities which occur on feeding a person following a period of starvation. It occurs when an extended period of catabolism ends abruptly with switching to carbohydrate metabolism. The metabolic consequences include:

· hypophosphataemia

· hypokalaemia

· hypomagnesaemia: may predispose to torsades de pointes

· abnormal fluid balance

These abnormalities can lead to organ failure.

Prevention

NICE produced guidelines in 2006 on nutritional support. Refeeding syndrome may avoided by identifying patients at a high-risk of developing refeeding syndrome:

Patients are considered high-risk if one or more of the following:

· BMI < 16 kg/m2

· unintentional weight loss >15% over 3-6 months

· little nutritional intake > 10 days

· hypokalaemia, hypophosphataemia or hypomagnesaemia prior to feeding (unless high)

If two or more of the following:

· BMI < 18.5 kg/m2

· unintentional weight loss > 10% over 3-6 months

· little nutritional intake > 5 days

· history of: alcohol abuse, drug therapy including insulin, chemotherapy, diuretics and antacids

NICE recommend that if a patient hasn't eaten for > 5 days, aim to re-feed at no more than 50% of requirements for the first 2 days.

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:15

Scoring systems for liver cirrhosis

For many years the Child-Pugh classification was used to classify the severity of liver cirrhosis. However, in recent years the Model for End-Stage Liver Disease (MELD) has been increasingly used, particularly patient's who are on a liver transplant waiting list

Child-Pugh classification

Score	1	2	3
Bilirubin (µmol/l)	<34	34-50	>50
Albumin (g/l)	>35	28-35	<28
Prothrombin time, prolonged by (s)	<4	4-6	>6
Encephalopathy	none	mild	marked
Ascites	none	mild	marked

Summation of the scores allows the severity to be graded either A, B or C:

· < 7 = A

· 7-9 = B

· > 9 = C

MELD

Uses a combination of a patient's bilirubin, creatinine, and the international normalized ratio (INR) to predict survival. A formula is used to calculate the score:

MELD = 3.78×ln[serum bilirubin (mg/dL)] + 11.2×ln[INR] + 9.57×ln[serum creatinine (mg/dL)] + 6.43

The 3-month mortality based on MELD scores:

· 40 or more: 71.3% mortality

· 30 - 39: 52.6% mortality

· 20 - 29: 19.6% mortality

· 10 - 19: 6.0% mortality

· < 9: 1.9% mortality

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:15

Vitamin C deficiency (scurvy)

Vitamin C (ascorbic acid) is found in citrus fruits, tomatoes, potatoes, Brussel sprouts, cauliflower, broccoli, cabbage and spinach. Deficiency (commonly called scurvy) leads to impaired collagen synthesis and disordered connective tissue as ascorbic acid is a cofactor for enzymes used in the production of proline and lysine. It is associated with severe malnutrition as well as drug and alcohol abuse, and those living in poverty with limited access to fruits and vegetables.

Symptoms and signs include:

· Follicular hyperkeratosis and perifollicular haemorrhage

· Ecchymosis, easy bruising

· Poor wound healing

· Gingivitis with bleeding and receding gums

· Sjogren's syndrome

· Arthralgia

· Oedema

· Impaired wound healing

· Generalised symptoms such as weakness, malaise, anorexia and depression

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:15

Abdominal incisions

Midline incision	· Commonest approach to the abdomen · Structures divided: linea alba, transversalis fascia, extraperitoneal fat, peritoneum (avoid falciform ligament above the umbilicus) · Bladder can be accessed via an extraperitoneal approach through the space of Retzius
Paramedian incision	· Parallel to the midline (about 3-4cm) · Structures divided/retracted: anterior rectus sheath, rectus (retracted), posterior rectus sheath, transversalis fascia, extraperitoneal fat, peritoneum · Incision is closed in layers
Battle	· Similar location to paramedian but rectus displaced medially (and thus denervated) · Now seldom used
Kocher's	Incision under right subcostal margin e.g. Cholecystectomy (open)
Lanz	Incision in right iliac fossa e.g. Appendicectomy
Gridiron	Oblique incision centered over McBurneys point- usually appendicectomy (less cosmetically acceptable than Lanz
Gable	Rooftop incision
Pfannenstiel's	Transverse supra pubic, primarily used to access pelvic organs
McEvedy's	Groin incision e.g. Emergency repair strangulated femoral hernia
Rutherford Morrison	Extraperitoneal approach to left or right lower quadrants. Gives excellent access to iliac vessels and is the approach of choice for first time renal transplantation.

Image sourced from Wikipedia

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:15

Antidiarrhoeal agents

Opioid agonists include

· loperamide

· diphenoxylate

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:15

Bile-acid malabsorption

Bile-acid malabsorption is a cause of chronic diarrhoea. This may be primary, due to excessive production of bile acid, or secondary to an underlying gastrointestinal disorder causing reduced bile acid absorption. It can lead to steatorrhoea and vitamin A, D, E, K malabsorption.

Secondary causes are often seen in patients with ileal disease, such as with Crohn's. Other secondary causes include:

· cholecystectomy

· coeliac disease

· small intestinal bacterial overgrowth

Investigation

· the test of choice is SeHCAT

· nuclear medicine test using a gamma-emitting selenium molecule in selenium homocholic acid taurine or tauroselcholic acid (SeHCAT)

· scans are done 7 days apart to assess the retention/loss of radiolabelled 75SeHCAT

Management

· bile acid sequestrants e.g. cholestyramine

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:15

Bilirubin

Bilirubin is a chemical by-product of the breakdown of heme, a component of red blood cells, and other hepatic heme-containing proteins, for example, myoglobin. The released heme is processed within macrophages and oxidized to form biliverdin and iron. Biliverdin is then reduced to form unconjugated bilirubin, which is released into the bloodstream.

Unconjugated bilirubin is bound to albumin in the blood and then taken up by hepatocytes, where it is conjugated, thus rendering it water-soluble. From hepatocytes, it is excreted into bile and thus enters the intestines to be broken down by intestinal bacteria. Bacterial proteases produce urobilinogen from bilirubin within the intestinal lumen, the majority of which is further processed by intestinal bacteria to form urobilin and stercobilin and excreted via the faeces. Around 10% of the bilirubin entering the intestinal system re-enters the portal circulation to be finally excreted via the kidneys in urine.

Raised levels of unconjugated bilirubin may occur as a result of haemolysis, which is to say a pre-hepatic source, for example, autoimmune-mediated haemolytic anaemia. Red blood cell breakdown exposes heme-containing proteins and, as discussed above, these are then processed to form unconjugated bilirubin.

Hepatocyte defects, such as a compromised hepatocyte uptake of unconjugated bilirubin and/or defective conjugation may occur in liver disease, or deficiency of glucuronyl transferase.

A mild glucuronyl transferase deficiency results in Gilbert's Syndrome, whilst a moderate to severe glucuronyl transferase deficiency may be seen in Crigler-Najjar Syndrome types I and II respectively. A transient glucuronyl transferase deficiency may also contribute to physiological neonatal jaundice.

Raised levels of conjugated bilirubin can result from defective excretion of bilirubin, for example, Dubin-Johnson Syndrome, or cholestasis.

Jaundice starts to appear when bilirubin reaches an excess of 35umol/l.

Cholestasis can result from a wide range of pathologies, which can be largely divided into physical causes, for example, gallstones, pancreatic and cholangiocarcinoma, or functional causes, for example, drug-induced, pregnancy-related and post-operative cholestasis.

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:15

Constipation

Constipation is a common primary functional disorder of the bowel but may, of course, develop secondary to another condition. It may be defined as defecation that is unsatisfactory because of infrequent stools (< 3 times weekly), difficult stool passage (with straining or discomfort), or seemingly incomplete defecation.

Features

· the passage of infrequent hard stools

Complications

· overflow diarrhoea

· acute urinary retention

· haemorrhoids

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:16

Diverticulosis

Diverticulosis is an extremely common disorder characterised by multiple outpouchings of the bowel wall, most commonly in the sigmoid colon. Strictly speaking the term diverticular disease is reserved for patients who are symptomatic - diverticulosis is the more accurate term for diverticula being present.

Risk factors

· increasing age

· low-fibre diet

Diverticulosis can present in a number of ways:

· painful diverticular disease: altered bowel habit, colicky left sided abdominal pain. A high fibre diet is usually recommended to minimise symptoms

· diverticulitis: see below for more details

Diverticulitis

One of the diverticular become infected. The classical presentation is:

· left iliac fossa pain and tenderness

· anorexia, nausea and vomiting

· diarrhoea

· features of infection (pyrexia, raised WBC and CRP)

Management:

· mild attacks can be treated with oral antibiotics

· more significant episodes are managed in hospital. Patients are made nil by mouth, intravenous fluids and intravenous antibiotics (typical a cephalosporin + metronidazole) are given

Complications of diverticulitis include:

· abscess formation

· peritonitis

· obstruction

· perforation

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:16

Gastro-oesophageal reflux disease: investigation

Overview

· poor correlation between symptoms and endoscopy appearance

Indications for upper GI endoscopy:

· age > 55 years

· symptoms > 4 weeks or persistent symptoms despite treatment

· dysphagia

· relapsing symptoms

· weight loss

If endoscopy is negative consider 24-hr oesophageal pH monitoring (the gold standard test for diagnosis)

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:16

Gastro-oesophageal reflux disease: management

Gastro-oesophageal reflux disease (GORD) may be defined as symptoms of oesophagitis secondary to refluxed gastric contents

NICE recommend that GORD which has not been investigated with endoscopy should be treated as per the dyspepsia guidelines

Endoscopically proven oesophagitis

· full dose proton pump inhibitor (PPI) for 1-2 months

· if response then low dose treatment as required

· if no response then double-dose PPI for 1 month

Endoscopically negative reflux disease

· full dose PPI for 1 month

· if response then offer low dose treatment, possibly on an as-required basis, with a limited number of repeat prescriptions

· if no response then H2RA or prokinetic for one month

Complications

· oesophagitis

· ulcers

· anaemia

· benign strictures

· Barrett's oesophagus

· oesophageal carcinoma

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:16

Hepatitis D

Hepatitis D is a single stranded RNA virus that is transmitted parenterally. It is an incomplete RNA virus that requires hepatitis B surface antigen to complete its replication and transmission cycle.

It is transmitted in a similar fashion to hepatitis B (exchange of bodily fluids) and patients may be infected with hepatitis B and hepatitis D at the same time.

Hepatitis D terminology:

· Co-infection: Hepatitis B and Hepatitis D infection at the same time.

· Superinfection: A hepatitis B surface antigen positive patient subsequently develops a hepatitis D infection.

Superinfection is associated with high risk of fulminant hepatitis, chronic hepatitis status and cirrhosis.

Diagnosis is made via reverse polymerase chain reaction of hepatitis D RNA. Interferon is currently used as treatment, but with a poor evidence base.

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:16

Inferior mesenteric artery

The IMA is the main arterial supply of the embryonic hindgut and originates approximately 3-4 cm superior to the aortic bifurcation. From its aortic origin it passes immediately inferiorly across the anterior aspect of the aorta to eventually lie on its left hand side. At the level of the left common iliac artery it becomes the superior rectal artery.

Branches

The left colic artery arises from the IMA near its origin. More distally up to three sigmoid arteries will exit the IMA to supply the sigmoid colon.

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:16

Iron studies

Serum iron

Total iron binding capacity (TIBC)

· transferrin

· raised in iron deficiency anaemia (IDA)

· raised in pregnancy and by oestrogen

Transferrin saturation

· calculated by serum iron / TIBC

Ferritin

· raised in inflammatory disorders

· low in IDA

Rarer tests

· transferrin receptors increased in IDA

Anaemia of chronic disease

· normochromic/hypochromic, normocytic anaemia

· reduced serum and TIBC

· normal or raised ferritin

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:16

Irritable bowel syndrome

NICE published clinical guidelines on the diagnosis and management of irritable bowel syndrome (IBS) in 2008

The diagnosis of IBS should be considered if the patient has had the following for at least 6 months:

· abdominal pain, and/or

· bloating, and/or

· change in bowel habit

A positive diagnosis of IBS should be made if the patient has abdominal pain relieved by defecation or associated with altered bowel frequency stool form, in addition to 2 of the following 4 symptoms:

· altered stool passage (straining, urgency, incomplete evacuation)

· abdominal bloating (more common in women than men), distension, tension or hardness

· symptoms made worse by eating

· passage of mucus

Features such as lethargy, nausea, backache and bladder symptoms may also support the diagnosis

Red flag features should be enquired about:

· rectal bleeding

· unexplained/unintentional weight loss

· family history of bowel or ovarian cancer

· onset after 60 years of age

Suggested primary care investigations are:

· full blood count

· ESR/CRP

· coeliac disease screen (tissue transglutaminase antibodies)

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:16

Peptic ulcer disease (perforation)

The symptoms of perforation secondary to peptic ulcer disease typically develop suddenly

· epigastric pain, later becoming more generalised

· patients may describe syncope

Investigations

· Although the diagnosis is largely clinical, UptoDate recommend that plain x-rays are the first form of imaging to obtain

· An upright ('erect') chest x-ray is usually required when a patient presents with acute upper abdominal pain

· This is a useful test, as approximately 75% of patients with a perforated peptic ulcer will have free air under the diaphragm

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:16

Pernicious anaemia

Pernicious anaemia is an autoimmune disorder affecting the gastric mucosa that results in vitamin B12 deficiency. It is helpful to remember that pernicious means 'causing harm, especially in a gradual or subtle way' - the symptoms of signs are often subtle and diagnose is often delayed.

Whilst pernicious anaemia is the most common cause of vitamin B12 deficiency, it's not the only cause. Other causes include atrophic gastritis (e.g. secondary to H. pylori infection), gastrectomy, malnutrition (e.g. alcoholism).

Pathophysiology

· antibodies to intrinsic factor +/- gastric parietal cells

o intrinsic factor antibodies → bind to intrinsic factor blocking the vitamin B12 binding site

o gastric parietal cell antibodies → reduced acid production and atrophic gastritis. Reduced intrinsic factor production → reduced vitamin B12 absorption

· vitamin B12 is important in both the production of blood cells and the myelination of nerves → megaloblastic anaemia and neuropathy

Risk factors

· more common in females (F:M = 1.6:1) and typically develops in middle to old age

· associated with other autoimmune disorders: thyroid disease, type 1 diabetes mellitus, Addison's, rheumatoid and vitiligo

· more common if blood group A

Features

· anaemia features

o lethargy

o pallor

o dyspnoea

· neurological features

o peripheral neuropathy: 'pins and needles', numbness. Typically symmetrical and affects the legs more than the arms

o subacute combined degeneration of the spinal cord: progressive weakness, ataxia and paresthesias that may progress to spasticity and paraplegia

o neuropsychiatric features: memory loss, poor concentration, confusion, depression, irritabiltiy

· other features

o mild jaundice: combined with pallor results in a 'lemon tinge'

o glossitis → sore tongue

Investigation

· full blood count

o macrocytic anaemia: macrocytosis may be absent in around of 30% of patients

o hypersegmented polymorphs on blood film

o low WCC and platelets may also be seen

· vitamin B12 and folate levels

o a vitamin B12 level of >= 200 nh/L is generally considered to be normal

· antibodies

o anti intrinsic factor antibodies: sensivity is only 50% but highly specific for pernicious anaemia (95-100%)

o anti gastric parietal cell antibodies in 90% but low specificity so often not useful clinically

· Schilling test is no longer routinely done

o radiolabelled B12 given on two occasions, firstly on its own, secondly with oral IF. Urine B12 levels are then measured

Management

· vitamin B12 replacement

o usually given intramuscularly

o no neurological features: 3 injections per week for 2 weeks followed by 3 monthly treatment of vitamin B12 injections

o more frequent doses are given for patients with neurological features

o there is some evidence that oral vitamin B12 may be effective for providing maintenance levels of vitamin B12 but it is not yet common practice

· folic acid supplementation may also be required

Complications other than the haematological and neurological features detailed above

· increased risk of gastric cancer

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:16

Vitamin A (retinol)

Vitamin A is a fat soluble vitamin.

Functions

· converted into retinal, an important visual pigment

· important in epithelial cell differentiation

· antioxidant

Consequences of vitamin A deficiency

· night blindness

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:16

Vitamin B3 (niacin)

Niacin is a water soluble vitamin of the B complex group. It is a precursor to NAD+ and NADP+ and hence plays an essential metabolic role in cells.

Biosynthesis

· Hartnup's disease: hereditary disorder which reduces absorption of tryptophan

· carcinoid syndrome: increased tryptophan metabolism to serotonin

Consequences of niacin deficiency:

· pellagra: dermatitis, diarrhoea, dementia

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:16

Vitamin B6 (pyridoxine)

Vitamin B6 is a water soluble vitamin of the B complex group. It is converted to pyridoxal phosphate (PLP) which is a cofactor for many reactions including transamination, deamination and decarboxylation.

Causes of vitamin B6 deficiency

· isoniazid therapy

Consequences of vitamin B6 deficiency

· peripheral neuropathy

· sideroblastic anemia

Diagram showing the biochemical role of vitamin B12 and vitamin B6

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:16

Vitamin C (ascorbic acid)

Vitamin C is a water soluble vitamin.

Functions

· antioxidant

· collagen synthesis: acts as a cofactor for enzymes that are required for the hydroxylation proline and lysine in the synthesis of collagen

· facilitates iron absorption

· cofactor for norepinephrine synthesis

Vitamin C deficiency (scurvy) leads to defective synthesis of collagen resulting in capillary fragility (bleeding tendency) and poor wound healing

Features vitamin C deficiency

· gingivitis, loose teeth

· poor wound healing

· bleeding from gums, haematuria, epistaxis

· general malaise

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:16

Zollinger-Ellison syndrome

Zollinger-Ellison syndrome is condition characterised by excessive levels of gastrin, usually from a gastrin secreting tumour usually of the duodenum or pancreas. Around 30% occur as part of MEN type I syndrome

Features

· multiple gastroduodenal ulcers

· diarrhoea

· malabsorption

Diagnosis

· fasting gastrin levels: the single best screen test

· secretin stimulation test

From <https://www.passmedicine.com/review/textbook.php?s=#>

Liver function tests

04 January 2021

23:14

ALP (Isolated) is physiologically raised in the 3rd trimester of pregnancy

plasma half-life of prothrombin factor 7 is approximately 6 hours

90% of Liver disease is preventable, with three quarters of people being diagnosed at a late stage.

Where Transferases (ALT/AST) >> ALP and GGT

· Consider a Hepatic cause

Where ALP and GGT >> Transferases (ALT/AST)

· Consider a Biliary / Obstructive cause

A standardised serum liver function test usually includes:

Bilirubin

Albumin

Transferases (alanine transferase (ALT); aspartate transferase (AST)

Alkaline phosphatase (ALP)

Gamma Glutamyltransferase (GGT)

On some testing panels GGT and AST have to been added on in addition to the standard panel. It is also useful to include a serum coagulation or INR when assessing liver function

Bilirubin is formed by the breakdown of haemoglobin within the reticuloendothelial system. This forms unconjugated bilirubin, which is water-insoluble and therefore needs to be bound to albumin, where it is taken up by the liver.

In the Liver bilirubin is conjugated to make it water-soluble. The majority of Conjugated bilirubin is excreted as bile acid via the bile ducts of the Liver. It is stored within the gallbladder and released into the small intestine where it aids in the breakdown of lipids. 95% of bile is reabsorbed in the terminal ileum to the Entrohepatic circulation.

From <https://mle.ncl.ac.uk/cases/page/16351/>

In general the total serum bilirubin is usually measured, but you can measure both the indirect (unconjugated) and direct (conjugated) portions.

The normal range is usually <21umol/L

From <https://mle.ncl.ac.uk/cases/page/16351/>

Unconjugated bilirubin

This usually is elevated due to increased bilirubin production OR decreased hepatic uptake/conjugation:

The commonest causes of raised unconjugated bilirubin in adults are:

· Gilbert’s syndrome:

o A genetic disorder where less of the enzyme that breaks down Bilirubin (UDP-glucuronyltransferase) is produced. It affects 5% of the population. There is an increase in the bilirubin often with fasting or concurrent illness.

o Confirmation of just a predominant unconjugated hyperbilirubinaemia makes the diagnosis of Gilbert’s syndrome virtually certain. This does not require any treatment and the patient can be completely reassured.

o Rarely does it cause a bilirubin above 68umol/L

· Haemolysis:

o The breakdown of red blood cells. There can by many causes for this and standard investigations for this would include: reticulocyte count, LDH, blood film, Haptoglobin, Direct coombs test

· Drug related, for example, the antibiotic Rifampicin impairs the uptake of Bilirubin

Conjugated Bilirubin

In healthy adults conjugated bilirubin is virtually absent. Levels usually start to become increased when the liver has lost approximately ½ of its excretory capacity. It is therefore usually a sign of liver disease, which may be acute or chronic in nature.

Common causes for elevated conjugated bilirubin include:

· Biliary obstruction at any level of the bile ducts

o Often secondary to gallstones in the common bile duct, but also from malignancy – commonly Cholangiocarcinoma or Pancreatic cancer

· Cholestatic drug reactions

o Potentially any drug, but commonly antibiotics such as Nitrofuratoin and Penicillin

· Autoimmune Cholestatic disease e.g. Primary Sclerosing Cholangitis (may occur at any level) and Primary Biliary Cirrhosis (intrahepatic ducts)

· Hepatitis of any origin where there is significant impairment in liver function

· Cirrhosis

ALT and AST

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) is measured in a liver function test profile. Both these enzymes live predominately in hepatocytes, whilst AST may also be found diffusely in cardiac and skeletal muscle, renal tissue, along with red blood cells. This means that ALT is in general more specific to the liver.

Injury to the liver, whether acute or chronic, will cause inflammation or damage to hepatocytes (but not necessarily cell death), leading to a release of these enzymes into the blood stream and resulting in a measureable increase in serum concentration of aminotransferases.

Therefore elevated transferase usually reflects a hepatitis of which there could be many causes.

Common causes of acute and chronic hepatitis are:

· Alcohol – including chronic alcohol abuse and Alcoholic hepatitis

· Non-alcoholic fatty liver disease (NAFLD)

· Viral Hepatitis – both acute and chronic

· Autoimmune Hepatitis

· Drug toxicity

· Ischaemia – this can be due to anything which suddenly causes a patient’s blood pressure to drop

· Metabolic liver disease (Wilson’s / Haemochromatosis)

Upper limits may vary between labs and the units that are used, but normal is usually considered to be less than 40IU/L.

There is no internationally recognised criteria but generally rises in aminotransferase can be thought as:

·      Mild (<5 upper limit of normal)

·      Moderate (5-10 upper limit of normal) 

·      Marked (> 10 upper limit of normal)

The degree of rise in transferase can help guide the underlying aetiology, although there is often significant overlap.

The diagram below illustrates the degree of ALT rise with associated disease.

A useful rule of thumb is that an ALT rise of greater than 1,000 IU/L reflects a significant acute liver injury and is typically only caused by the following:

· Ischaemia

· Drugs (Most commonly Paracetamol)

· Viruses (Hepatitis A, B, C and E)

Examining the ratio of AST to ALT can also be helpful in determining the underlying cause. In alcohol related liver disease patients are often nutritionally deficient in vitamin B6. This effects the activity of ALT, resulting in reduced concentrations, thus typically resulting in an AST/ALT ratio of >2 in alcoholic liver disease; whilst an AST/ALT ratio of <1.0 would be more suggestive of non-alcoholic liver disease.

The circulation half-life for ALT is around 47 hours.

From <https://mle.ncl.ac.uk/cases/page/16748/>

ALP

Alkaline phosphatase (ALP) is another enzyme, but which predominately comes from cells that line the biliary tract, however it is also present in bone and the placenta. Therefore it may be elevated physiologically or pathologically.

A normal ALP is generally <130 IU/L

Physiological causes include:

· 3rd Trimester of pregnancy

· Increase bone turnover – adolescents during periods of growth

Pathological causes include:

· Hepatic:

o Bile duct obstruction – stones, malignancy

o Primary Sclerosing Cholangitis (PSC)

o Primary Biliary Cirrhosis (PBC)

o Drug induced cholestasis (antibiotics, anabolic steroids)

· Extra-hepatic:

o Bone disease: Factures, Pagets disease and bone metastasis

GGT

The enzyme Gamma-glutamyltransferase (GGT) is present in cell membranes of bile ducts, gallbladder, kidneys, pancreas, spleen and heart. It may be raised in all types of liver disease, however when paired with an elevated ALP it is highly suggestive of hepatobiliary source.

A normal GGT is usually < 70 unit/L

Isolated ALP rises can and do occur in PSC and PBC. However you should also be alert for other sources, in particular for bone metastasis. Isolated GGT is seen in alcohol abuse, as well as COPD and renal failure.

Cholestasis enhances the synthesis and release of ALP. The half-life of ALP is around a week; therefore levels may rise quickly in bile duct obstruction and decrease slowly following resolution.

Prothrombin

The Prothrombin Time (PT) is a measure of the function of the extrinsic and common coagulation pathways. It represents the time in seconds for the patient’s plasma to clot after the addition of calcium and thromboplastin (an activator in the extrinsic pathway).  Another way to represent this is the Internationalised Normalised Ratio, which standardises how the PT is measured - difficult labs have different ways of measuring PT, meaning it is difficult to compare PT’s across different laboratories.

The PT and Internationalised Normalised Ratio (INR) are both useful for measuring Liver synthetic function because clotting factors II, V, VII, IX, and X are produced in the Liver.  Therefore if the liver is not able to produce these clotting factors due to dysfunction this is reflected in a prolonged PT/INR.

The PT/INR is particularly useful in acute liver injury as factor VII has a short half-life – around 6 hours. Therefore it is useful in acute or fulminant liver failure as a way to monitor the progression of damage or impairment to the liver.

PT and INR may be prolonged in chronic liver disease but not until approximately 80% of the livers synthetic function is compromised. It is therefore a useful indicator of advanced liver disease, particularly in decompensated liver cirrhosis and is often included in prognostic scoring systems.

One important thing to consider is that while a prolonged PT may indicate liver synthetic dysfunction, it can be prolonged for other reasons. In particular deficiency in fat-soluble vitamin k, which is used in the generation of factors II, VII, IX, and X, can be responsible. This is particularly true in cases of obstructive jaundice where reduced bile acid excretion impairs intestinal absorption of fat-soluble vitamins.

Acute liver failure (ALF) is loss of liver function at that occurs rapidly in days or weeks in the absence of any underlying chronic liver disease. It is characterized by jaundice, coagulopathy (prolonged PT/INR) and hepatic encephalopathy. Hepatic Encephalopathy is essential to fulfil the diagnosis of ALF.

ALF can be further subdivided into Hyperacute, Acute or Subacute.

· Hyperacute - Encephalopathy occurs within 7 days of onset of jaundice

· Acute liver failure – 8 to 28 days from jaundice to encephalopathy

· Sub acute failure - Hepatic encephalopathy occurs within 5-12 weeks of onset of jaundice.

· Severe Acute liver injury – Elevated transferases, prolonged PT and jaundice. But NO hepatic encephalopathy

In chronic liver disease there is a duration of greater than 28 weeks before the onset of hepatic encephalopathy.

Acute on chronic liver disease, or decompensating liver disease share features of acute liver failure clinically – we know that ¾ of patients present with advanced liver disease, their first presentation may therefore be with jaundice, coagulopathy and hepatic encephalopathy.

Clues to suggest underlying chronic liver disease rely on a thorough clinical assessment, which includes a full history.  Clinical examination to look for signs secondary to chronic liver disease is particularly helpful (see later).  Portal hypertension is more common in advanced chronic liver disease (but may also occur in the acute setting), these may be evident clinically, biochemically (Platelets  < 150 due to hypersplenism) or radiologically.

From <https://mle.ncl.ac.uk/cases/page/16558/>

Consequences of portal hypertension include:

Oesophageal and Gastric Varices

Abdominal Ascites

Peripheral oedema

Hepatic Encephalopathy

Low Platelets (due to hypersplenism)

         Antimitochondrial antibody - PBC

         Anti-smooth muscle antibody / anti LKM1 / Antinuclear antibody – Autoimmune Hepatitis

         pANCA – PSC

From <https://mle.ncl.ac.uk/cases/page/16583/>

         Elevated IgA – often associated with fatty liver disease -such as alcohol or NAFLD (Non-Alcoholic Fatty Liver Disease)

         Elevated IgM – often associated with Primary Biliary Cirrhosis

         Elevated IgG – often associated with Autoimmune Hepatitis

From <https://mle.ncl.ac.uk/cases/page/16583/>

¡  Serum ferritin and transferrin saturation – elevated in Haemochromatosis

¡  Copper/Caeruloplasmin – Wilson's disease

¡  Alpha-1 antitrypsin (A1AT) – Hereditary disorder

Alpha-fetoprotein (AFP) – this should not form part of the liver screen but instead is used in screening for Hepatocellular Carcinoma – a common sequelae of Cirrhosis, and chronic Hepatitis B and C infection.

From <https://mle.ncl.ac.uk/cases/page/16583/>

Haemochromatosis

04 January 2021

23:52

Haemochromatosis

A disorder that results in iron overload, which may affect many organs. There are two types – primary and secondary.

Primary

An inherited disorder, the most common being autosomal recessive caused by a defect in the HFE gene, sometimes called HFE Haemochromatosis. It was thought this was the only gene associated with Haemochromatosis, however it is now know that there are other gene associations.

Haemochromatosis.org.uk

This is the UK’s most common genetic condition.

The two known mutations of HFE are C282Y and H63D. Testing for these is simple and cheap. But there are other rare genes that may cause disease

Whilst this is an autosomal recessive condition, clinically things can be a bit more complex – this is because gene expression (penetrance) varies. E.g. just because you have two copies of the defective gene does not mean you will definitely develop the clinical condition.

· C282Y/C282Y Homozygous gives a 95% risk of iron overload

· C282Y/H63D compound heterozygotes gives around 4% risk (increased risk with increased alcohol intake, viral hepatitis)

· H63D/H63D Homozygous is least likely to cause iron overload

All these genes lead to increased intestinal absorption of iron.

Patients are often identified incidentally due to abnormal liver tests (elevated ALT), abnormal imaging (fatty liver, iron overload in liver) or elevated serum ferritin (see later). They can  present with vague symptoms or advanced disease

The main symptoms patients may present with are:

1. Joint pain – especially of the hands and fingers

2. Fatigue

3. Mood disorders – depression / anxiety / mood swings

Other symptoms include abdominal pain, palpations, shortness of breath, infertility, hair loss and amenorrhoea.

These symptoms usually appear later on in the disease – around age 40-60 in males, and post menopausal for females.

Advanced disease may present with diabetes, bronzing of the skin, hepatomegaly/cirrhosis and arthropathy of the 2nd and 3rd metacarpophalangeal joints

If there is genetic expression then this is likely to be reflected in elevated serum ferritin and transferrin saturations.

Secondary

Iron overload due to parental iron-overload e.g. multiple blood transfusions or IV iron replacement. It can be from several haematological disorders e.g. myelodysplastic syndrome

Serum Ferritin (SF)

This is a measurement of the protein ferritin in the blood. SF usually correlates well with iron storage.

The normal range males is 15-300 µg/l and females 15-200 µg/l

In Haemochromatosis the ferritin is often (but not always) in 1000’s

It is however important to note that ferritin can also be significantly raised in those with chronic alcohol abuse or have NAFLD as part of the metabolic syndrome. It is also an acute phase protein and can be raised in inflammatory conditions and malignancy.  Therefore an additional blood test called transferrin saturations is also tested.

Transferrin Saturation (TS)

A glycoprotein that binds free iron in the bloodstream. When low it means that there is not much iron available. Conversely when high it indicates that the free iron levels are high.

The normal range for males is 16-50%, for females this is 16-45%

Diagnosis

Patients with elevated SF and T/S should undergo genetic screening for the above genes; those with a ferritin greater than 1000 µg/l should be referred urgently to secondary care to exclude Cirrhosis.

Liver function tests, imaging such as ultrasound and/or fibroscan should be used to assess degree of liver damage.

Diagnosis of HFE Haemochromatosis should not be based on C282Y homozygosity. It requires evidence of increased iron stores.

Those with HFE genotype, but not gene expression, e.g. normal SF and TS should have annual iron studies.

Treatment

There are two main phases to treatment:

1.     Acute iron removal – this is done via venesection (approx. 450ml of blood is removed). This will reduce the SF by approx. 20-25 µg/l. This is continued until SF are 50-100 µg/l.. Treatment may be required for 12 to 18months, weekly to 2 weekly.

2.     Maintenance phase – 2-4 venesections a year to keep SF 50-100 µg/l

Some symptoms may improve with venesection

Patients with Cirrhosis and haemochromatosis are at a significant increased risk of Hepatocellular Carcinoma and should be screened every 6 months with ultrasound imaging and serum AFP.

Haemochromatosis.org.uk

A patient with confirmed genetic haemochromatosis should be offered genetic counselling and also genetic screening for any first-degree relatives – siblings will have a ¼ chance of being homozygote. If the patient has children, then assuming a patients partner does not carry the gene then any children will be carriers.

From <https://mle.ncl.ac.uk/cases/page/16603/>

Wilson's disease

04 January 2021

23:53

Wilson’s disease is a rare progressive genetic disorder, which results in accumulation of copper in the body’s tissues. In particular it affects the brain, liver and cornea of the eyes.  Untreated it may lead to liver fibrosis and cirrhosis, along with central nervous system dysfunction.

There are 500 gene mutations known about. These result in dysfunction in Wilson’s ATPase, which usually moves copper from along intracellular membranes in the liver. The defective ATPase results in accumulation of copper in the liver, resulting in damage. Over time as the liver becomes damaged the copper is released into the blood and causes other end organ damage.

Damage may begin to occur as early as age 6, but often does not become apparent until teenage years (range 5 to 35).

Patients may present with:

Liver dysfunction (most common presentation):

·      Decompensated liver cirrhosis

·      Acute liver failure  (often associated with renal failure and haemolytic anaemia)

Central nervous system (usually have established liver disease):

·      Asymmetrical tremor in ½ patients with CNS dysfunction

·      Poor co-ordination and clumsiness

·      Speech and language problems

·      Neuropsychiatric illness – commonly severe depression or neurotic behaviours

Ophthalmological

·      Kayser-Fleischer ring present in 95% of those with neurological disease (seen on slit-lamp), 50% of those without. May occur in other diseases.

·      Sun-flower cataracts – seen on slit lamp. Do not impair vision

Diagnosis.

Consider in any patient of any age with unusual liver or neurological abnormalities. There is no one best test for diagnosis.

Presence of Kayser-Felischer ring and low serum caeruloplasmin (<0.1g/L) is enough to establish diagnosis.

Caeruloplasmin is a protein made in the liver that stores and carries copper around the blood. This may be low in Wilson’s as copper is not able to bind to the protein causing instability. Serum Caeruloplasmin is can be affected by many factors and is not diagnostic on it’s own.

Other markers of disease include 24hour urinary copper, serum free copper and hepatic copper (liver biopsy).

A scoring system also exists to help with diagnosis.

Genetic screening is complex, many patients are compound heterozygotes (carry two different defective genes) and it can take many months to complete.

Treatment

Treatment is life-long. It involves using medication to either promote urinary excretion or to decrease intestinal absorption. The commonest medication used is D-Penicillamine.

Genetics are complex due to the number of gene variations, but essentially siblings (25% risk) and any offspring (0.5% risk) should be offered genetic screening.

From <https://mle.ncl.ac.uk/cases/page/16604/>

SAAG serum to ascites albumin gradient

05 January 2021

00:02

A serum to ascites albumin gradient (SAAG) can help you differentiate the underlying cause of ascites.

· The serum-to-ascites albumin gradient (SAAG) accurately identifies the presence of portal hypertension and is more useful than the protein-based exudate/transudate concept

· The SAAG is easily calculated by subtracting the ascitic fluid albumin value from the serum albumin value, which should be obtained the same day. The SAAG generally does not need to be repeated after the initial measurement.

· The presence of a gradient ≥11 g/L predicts that the patient has portal hypertension with 97 percent accuracy

· This is due to increased hydrostatic pressure within the blood vessels of the hepatic portal system, which in turn forces water into the peritoneal cavity but leaves proteins such as albumin within the vasculature.

· A gradient <11 g/L indicates that portal hypertension is not the primary cause of ascites

· The following table illustrates some different causes of ascites which are associated with a high or low SAAG:

From <https://mle.ncl.ac.uk/cases/page/17267/>

Child Pugh score

05 January 2021

00:07

Child Pugh score is a grading system of cirrhosis and risk of variceal bleeding, ranging from 5-15. The grading can be used to predict mortality and quantify need for liver transplantation. Risk of variceal bleeding is much higher if the score is >8.

Mr Wilson’s Child-Pugh score is 11, which means he has Child-Pugh class C cirrhosis. This signifies he has a higher risk of variceal bleeding and higher mortality rate (1 year survival is 45% compared with 100% & 80% for Child-Pugh A & B respectively).

From <https://mle.ncl.ac.uk/cases/page/17271/>

Glasgow-Blatchford score

05 January 2021

00:10

Glasgow-Blatchford score. This is a prognostic score to assess the likelihood that Mr Wilson will require an intervention such as endoscopy or blood transfusion following his upper GI bleed.

Patients with a Glasgow-Blatchford score of 0 should be considered for discharge and subsequent outpatient endoscopy. Patients with a score >0 should be considered for endoscopy. This is shown below:

This patients scores 10 (4 for urea of 12.1, 3 for Hb 104, 0 for BP, score 1 for malaena and 2 for hepatic disease).

From <https://mle.ncl.ac.uk/cases/page/17274/>

Summary

05 January 2021

12:46

After blood tests

most important next step in NAFLD is to stage the disease; this helps stratify severity and those that should be managed in primary or secondary care. Most commonly in primary care this is done using either: FIB 4 score NAFLD score Tend to use FIB 4 in Newcastle; get students to calculate FIB 4 https://www.mdcalc.com/fibrosis-4-fib-4-index-liver-fibrosis Answer =1.24 Those with a FIB 4 65) have a low risk of advanced fibrosis and therefore can be managed in primary care. Management from the GP should concentrate on weight loss and management of metabolic risk factors including good diabetic control. Weight loss may include increasing exercise, decrease calories, use of a Mediterranean diet. Patients may find groups or apps helpful in this (this is covered in more detail in the NAFLD lecture). Also emphasis that if patient loses >10% of body weight can have complete resolution of inflammation Bloods should be repeated at least 3 yearly (but normally performed on an annual basis) and a FIB 4 recalculated

NICE guidelines suggest any patient who drinks > 50 units a week should be screened for significant liver disease with a fibroscan or bloods such as ELF test (estimation of liver fibrosis – blood test which looks for markers of fibrosis in the blood and gives an estimation of overall scarring)

Cirrhosis:

All patients with cirrhosis should be screened for osteoporosis with a DEXA scan

- Screened for varices with an OGD

- All patients (who would be fit enough to be considered for treatment) require 6 monthly HCC surveillance with USS (and most also measure alpha-feto protein

ascites/ peripheral oedema -

This is normally done with diuretics, usually introduce spironolactone first and then add in furosemide if not relieved on spironolactone alone

- This requires close monitoring of renal function and particularly sodium between increments of diuretics

- Some patients develop refractory ascites (persistent ascites despite maximal doses of diuretics) or renal function/ hyponatraemia preclude increasing diuretic dose further

- An option in these patients is large volume paracentesis (drainage of ascites) done as a day case procedure and can be repeated every few weeks

- If requiring regular paracentesis can consider TIPSS (transjugular intrahepatic portosystemic shunt) as long as liver synthetic function good and not had episodes of encephalopathy (as risk of encephalopathy significantly increases post TIPSS). If TIPSS contraindicated alternative would be to consider liver transplant

Liver transplantation criteria for chronic liver disease include:

- Poor synthetic function; this is assessed by the use of UKELD; this is a score that takes into account bilirubin, INR, creatinine and sodium https://www.mdcalc.com/unitedkingdom-model-end-stage-liver-disease-ukeld A UKELD of 49 or more is used as a threshold for eligibility; this confers a 9% chance of death within a year without transplant

- Persistent encephalopathy

- Refractory ascites (not suitable for TIPSS)

- Hepatocellular cancer – there are size criteria for this to be eligible must be 1 lesion < 5cm or can have up to 5 lesions with all lesions < 3cm

If considering transplant, patients are put forward for an assessment where lots of factors are taken

into account including overall fitness, other co-morbidities etc. If accepted for transplant they are

then placed on the transplant waiting list.