Achalasia

- caused by loss of ganglion cells within the esophageal myenteric plexus
- incidence 1:100,000
- presents at age between 25 and 60 years
- defined as reduced or absence of peristalsis and failure of lower esophageal sphincter to relax when swallowing
- presents with dysphagia, regurgitation, chest pain (esophageal spasm) and weight loss
- patient with advanced achalasia are at risk for bronchitis, pneumonia or lung abscess from chronic regurgitation and aspiration
- differential diagnoses are diffuse esophageal spasm (DES), Chagas' disease and pseudoachalasia (tumor infiltration)
- diagnosed by barium swallow X ray (dilated esophagus with poor emptying and air fluid level, tapering at the LES giving a beak-like appearance) and esophageal manometry (impaired LES relaxation and absent peristalsis)
- treatment: endoscopic pneumatic dilatation of LES (efficacy 32-98%), intra-sphincteric injection of botulinum toxin or Heller's cardiomyotomy 
- increased risk of esophageal squamous cell cancer secondary to prolonged stasis esophagitis

Non alcoholic fatty liver disease (NAFLD)

- prevalence range from 14-20%
- should always be considered in obese individuals with abnormal liver function test (raised ALT or AST) without evidence of alcohol excess
- often asymptomatic but hepatic enlargement due to lipid deposition within hepatocyte (making them appear bright on ultrasound) can lead to RUQ pain
- abnormal ferritin values are seen in 50% of patients with NASH, and may be a marker of insulin resistance in NASH
- liver biopsy: macrovesicular steatosis with occasional microvesicular fat
- rapid weight loss has been shown to increase fat deposition in liver and precipitate NASH
- weight loss of 1kg/week and exercise with an initial target loss of 10% bodyweight has been shown to be effective at restoring normal liver function

Coeliac disease

- T cell mediated autoimmune disease of small bowel in which prolamine intolerance causes villous atrophy and malabsorption
- a.k.a gluten sensitive enteropathy
- 95% HLA DQ2 and HLA DQ8
- prevalence : 1 in 300-1500 (more common in Irish)
- occurs at any age (peaks in infancy and 50-60)
- presents with steatorrhea, diarrhea, abdominal pain, bloating, aphthous ulcer, weight loss, iron deficiency anemia, osteomalacia, failure to thrive
- associated with dermatitis herpetiformis
- diagnosis: IgA endomysial antibodies , alpha-gliadin antibodies or anti-transglutaminase antibodies (IgG if IgA deficient - 10% of Coeliac disease)
- duodenal/jejunal biopsy (gold standard): subtotal villous atrophy, hypertrophied crypts of Lieberkuhn, increase in intraepithelial lymphocytes (biopsy reverse/improvement with a gluten free diet)
- treatment: lifelong gluten free diet (wheat, barley, rye, oats)
- complications: risk of malignancy (esophageal, gastric, small bowel), anemia, hyposplenism, lactose intolerance, GI T cell lymphoma (suspect if refractory symptom or weight loss)

Alpha-1 antitrypsin deficiency

- autosomal recessive
- defective gene in chromosome 14
- alpha-1 antitrypsin protein is synthesized by hepatic cells and released into circulation. In lungs, its primary function is to inactivate neutrophil elastase (enzyme released during phagocytosis in alveolus)
- encoded by protease inhibitor (Pi) locus
- most common (90%) allele is M (PiM). Normal is homozygous (PiMM)
- PiZZ have only 15-20% of normal blood alpha-1 antitrypsin level, which is severe
- Heterozygotes (PiMZ, PiMS, PiSZ) have less severe phenotypes
- smoking is the greatest risk factor for development of emphysema in adults with alpha-1 antitrypsin deficiency
- lung compliance increased in emphysema
- majority of patients with clinical liver disease are homozygotes with PiZZ phenotype, which can produce jaundice and liver problems in neonates within few days of birth

Spontaneous bacterial peritonitis

-complication of ascites, diagnosed by ascitic fluid examination which revealed a neutrophil count of  > 250 cells/ml
- should be suspected in any ascitic patient who clinically deteriorate, fever and pain can be absent
- abdominal tenderness in more than 50% SBP
- speculated that the infective organism may leak into ascitic fluid via blood or from intestinal overgrowth
- typically caused by aerobic gram negative organism (50% being E.coli)
- treatment : cefotaxime

Hepatitis B

- hepatitis B is a hepadnavirus
- HbsAg : first detectable antigen in acute infection but also detectable in chronic infection.
- HbeAg : best marker of infectivity. It denotes viral replications
- anti-HBc (IgM) and HBsAg suggest acute infection. When infection resolves, HBsAg becomes negative and anti-HBc (IgG) is positive
- vaccinated patient : HBsAg is negative and anti-HBs is positive (anti-HBc IgG negative in vaccinated patient but positive in patient recovered from hepatitis B infection)
- most sensitive index of viral replication is HBV DNA
- In pre-core hepatitis B mutant, patient unable to produce HbeAg but high level of viral replication equivalent to eAg positive HBV (highly infectious)
- persistence of HbsAg for more than 6 months defines carrier status and occurs in 5-10% of infections
- HBV DNA and HBeAg levels are measured in response to therapy and undetectable levels would be considered successful treatment
- chronic HBV may respond to PEG interferon alfa-2a or other antivirals
- interferon is indicated for treatment of chronic hepatitis B in e antigen positive patients but is contraindicated for patients with decompensated liver disease
- lamivudine is an inexpensive, safe and effective drug for suppression of hepatitis B virus. Resistance occurs in 15% of patients in 1 year and 60% in 4 years. Adevofir is second line drug for lamivudine resistant hepatitis B virus

Primary biliary cirrhosis (PBC)

- interlobular bile ducts are damaged by chronic granulomatous inflammation causing progressive cholestasis, cirrhosis and portal hypertension
- 90% are women in age range 40-50 years
- serum AMA (anti-mitochondrial antibodies) subtype M2 in 95%
- associated with autoimmune disorders (Sjogren, scleroderma, thyroid disorder)
- pruritus is earliest symptom, preceding jaundice by a few years
- back pain can be prominent in advanced PBC due to osteomalacia from malabsorption or hepatic osteodystrophy. Osteoporosis is common.
- palmar xanthoma, tuberous xanthomas are seen
- raised ALP, increased serum cholesterol, raised IgM levels
- liver biopsy : granulomas surrounding bile ducts in early disease later progressing to cirrhosis
- treatment: ursodeoxycholic acid and replacement of vitamin A,D,E and K
- median survival overall is 7-10years, reduced to 2 years in presence of jaundice

Coeliac disease

- a.k.a gluten sensitive enteropathy
- caused by an immunological reaction to gliadin fraction of wheat and other cereals
- 95% HLA DQ2 and HLA DQ8
- gliadin provokes an inflammatory response which results in partial or total villous atrophy in proximal small bowel
- presents with diarrhea, oral ulcer, weight loss, growth retardation, abdominal pain and anemia
- associated with dermatitis herpetiformis and IgA deficiency
- increased risk of all GI malignancy, especially small bowel lymphoma and esophageal CA
- diagnosis by IgA anti-endomysial antibodies 
- duodenal/jejunal biopsy shows hypertrophied crypts of Lieberkuhn, villous atrophy, degenerated surface epithelial cells and increase in intraepithelial lymphocytes
- treatment:gluten free diet

MALT lymphoma

- third most common type of non Hodgkin lymphoma (gastric B cell lymphoma)
- most commonly found in stomach
- associated with Helicobacter pylori infection
- treatment: H.pylori eradication, if failed, chemotherapy
- complications: paraprotein formation and pseudohyponatraemia

Congenital hyperbilirubinaemias

Unconjugated
 - Gilbert's syndrome
 - Criggler-Najjar syndrome
Conjugated
 - Dubin-Johnson syndrome
 - Rotor's syndrome

Gilbert's syndrome
- most common familial hyperbilirubinemia, 2-7% of population
- hepatic glucuronidation is 30% of normal
- reduced levels of UDP-glucuronosyl transferase (UGT-1) activity
- raised unconjugated bilirubin on fasting, and during mild illness
- bilirubin levels are reduced by enzyme inducer (eg: phenobarbitone)
- absence of bilirubin in urine(unconjugated bilirubin is tightly bound to albumin, thus cannot cross the glomerulus)

Criggler-Najjar syndrome
- very rare
- type II (autosomal dominant) - decreased UDP-GT
- type I (autosomal recessive) - absence of UDP-GT

Dubin-Johnson syndrome (autosomal recessive) & Rotor's syndrome (autosomal dominant)
- due to defects in bilirubin handling in liver
- good prognosis
- liver is black owing to melanin deposition

Primary sclerosing cholangitis

- disorder of unknown cause characterised by non malignant non bacterial inflammation, fibrosis, and stricture of the intra and extrahepatic bile ducts
- associated with ulcerative colitis
- more common in men (70%) and average age of 40
- presents with fluctuating jaundice, pruritus and cholangitis
- positive p ANCA
- raised ALP initially followed by raised bilirubin, hypergammaglobulinaemia
- ERCP: multiple strictures in biliary system
- cholangiogram: intrahepatic and extrahepatic duct strictures ('beaded' appearance)
- 10% risk of cholangiocarcinoma
- treatment: ursodeoxycholic acid, liver transplantation (only proven long term treatment)

Whipple disease

- extremely rare systemic infectious disease caused by Trophyrema whippeli (actinomycetes)
- affects middle aged while males
- presents with arthralgia/arthritis (seronegative arthropathy ~70%), diarrhea (70%), abdominal pain, fever and skin darkening
- severe malabsorption results in weight loss (90%) and along with fatigue and weakness caused by anemia
- also heart, lung, eye and brain involvement
- oculomasticatory myorrhythmia is characteristic
- small bowel (jejunal) biopsy: PAS positive macrophages in lamina propria
- most lesions (except cerebral) are reversible on prolonged antibiotic therapy
- treatment: amoxicillin, tetracycline, cotrimoxazole for 1 year

Pseudomembranous colitis

- acute exudative infection of colon caused by Clostridium difficile
- Clostridium difficile produce 2 types of toxin: type A is enterotoxin, type B is cytotoxic
- risk factor: antibiotic treatment (including clindamycin, ciprofloxacin, ampicillin, amoxicillin, cephalosporin)
- Greatest risk = ciprofloxacin
- symptoms varies from mild self limiting diarrhea to acute fulminating toxic megacolon
- tissue culture, ELISA and PCR help detect C.difficile toxin (CDT)
- treatment: stop the antibiotic, metronidazole or oral vancomycin

Non alcoholic steatohepatitis (NASH)

- commonest cause of a persistently raised ALT in patient with no risk factors of chronic liver disease
- also raised AST and GGT
- most patients are asymptomatic
- commoner in patients with obesity, diabetes and hypercholesterolemia (metabolic syndrome)
- diagnosis is by liver biopsy which shows increased fat deposition and necro-inflammatory response to hepatocytes
- ultrasound: hyperechogenicity or 'bright liver'
- management: aggressive weight loss, strict control of hypertension, diabetes and hyperlipidemia

VIPoma

-a.k.a Verner Morrison syndrome or WDHA syndrome
- endocrine tumor, usually originate from pancreas, producing vasoactive intestinal peptide (VIP)
- WD: watery diarrhea
- H: hypokalemia
- A: achlorhydia
- acidodis, vasodilatation, hypercalcemia, hyperglycemia

autoimmune hepatitis

- inflammatory liver disease of unknown cause characterised by suppressor T cell defects with autoantibodies directed against hepatocyte surface antigens
- 25% present with acute hepatitis and signs of autoimmune disease (fever, malaise, urticarial rash, polyarthritis, pleurisy or glomerulonephritis)
- Type I: occur in associated with other autoimmune disorder. Positive antinuclear antibodies, anti smooth muscle autoantibody (ASMA) and anti-actin antibodies
- Type II: occurs in association with anti liver/kidney mircosomal (LKM) antibodies. Most frequently in girls and young women.
- Type III: occurs in association with anti soluble liver-kidney antigen
- Liver biopsy : necroinflammatory process (mononuclear infiltrate of portal and periportal areas & piecemeal necrosis, fibrosis or cirrhosis)
- Treatment: prednisolone followed by azathioprine, or liver transplantation

Bile acid malabsorption

- can occur in long standing Crohn's disease (which involves terminal ileum) / ileal resection
- increased bile acids in colon reduce absorption of water and electrolytes and at higher concentration induce colonic secretion and increase motility.
- diagnosis by SeHCAT test (radiolabelled bile acid analogue is administered and percentage retention at 7 days is measured - less than 19% is abnormal)
- can be diagnosed by 14C glycolate test also
- treatment: cholestyramine

Carcinoid tumor

- arise from enterochromaffin cells that are located predominantly in gastrointestinal mucosa
- carcinoid syndrome occurs in 5% of carcinoid tumor (with liver metastasis)
- associated with cardiac abnormality (TS/TR, PS/PR - accumulation of fibrous tissue in heart)
- presents with flushing, bronchospasm, diarrhea
- can present with acute appendicitis (obstruction of lumen by carcinoid)
- Pellagra syndrome is a complication (3Ds - dementia, diarrhea and  dermatitis). Because carcinoids utilise tryptophan, a nicotinamide precursor - causing nicotinic acid deficiency.
- Investigations: urinary 5-HIAA (100% specificity), plasma chromogranin A (100% sensitivity), ultrasound liver
  (Foods that can interfere the test includes bananas, eggplant, avocado and walnuts - avoid for 3 days   before the test)
- Treatment : octreotide, appendicectomy, hepatic artery ligation/embolization

Tropical sprue

- most common in Caribbean and far east
- severe malabsorption (2 or more substance) accompanied by diarrhea and malnutrition
- presents with diarrhea, anorexia, abdominal distension, weight loss and steatorrhea
- work up : detailed history (travel history), D-xylose absorption test, jejunal biopsy (blunting/atrophy of villi, with subepithelial lymphocytic infiltration)
- megaloblastic anemia in more than 50% of cases
- treatment : folic acid supplementation, IM vitamin B12, tetracycline for 6 months