Sandbox:Akshun

• Treatment should be initiated promptly once the diagnosis has been made.
• The optimal duration of treatment is not known; controlled data are limited.
• As a general rule, a prolonged course of treatment should be expected.
• Folic acid should be given for at least 3 months and up to 1 year depending on clinical response.
• Antibiotic treatment has been given for periods between 2 weeks and 1 year, but most experience shows good outcomes with 3 to 6 months of treatment.
• Vitamin B12 supplementation is also recommended if symptoms last more than 4 months or in the presence of low vitamin B12 levels, regardless of symptom duration.

Pathology

• Tropical sprue (TS) causes mucosal changes throughout the digestive tract.
• Histopathological analysis shows:
  • Marked villous atrophy of small bowel
  • Decrease in total absorptive surface area
  • Decreased absorption of long-chain fatty acids causes steatorrhea
  • Decreased protein absorption
  • Protein loss through the leaky mucosal membrane

Gastrointestinal stromal tumors

KIT gene mutation

PDGFRA mutation

Wild type (absence of KIT/PDGFRA)

Exon 9,13 & 17

Exon 11

Mutant succinate dehydrogenase

Uncontrolled KIT signalling

KIT receptor mutation

Dysfunction of electron transport mitochondria

Defective oxidative phosphorylation

Abnormal stabilization of HIF

Classification of pain in the abdomen based on etiology Disease Clinical manifestations Diagnosis Comments Symptoms Signs Abdominal Pain Fever Rigors and chills Jaundice Diarrhea GI Bleed Hypo- tension Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Abdominal causes Inflammatory causes Pancreato-biliary disorders Acute suppurative cholangitis RUQ + + + − − + + + N Abnormal LFT WBC >10,000 Ultrasound shows biliary dilatation/stents/tumor Septic shock occurs with features of SIRS Acute cholangitis RUQ + − + − − − − − N Abnormal LFT Ultrasound shows biliary dilatation/stents/tumor Biliary drainage (ERCP) + IV antibiotics Acute cholecystitis RUQ + − + − − − − − Hypoactive Hyperbilirubinemia Leukocytosis Ultrasound shows gallstone and evidence of inflammation Murphy’s sign Acute pancreatitis Epigastric + − ± − − ± + + N Increased amylase / lipase Ultrasound shows evidence of inflammation CT scan shows severity of pancreatitis Pain radiation to back Chronic pancreatitis Epigastric − − ± + − − − − N Increased amylase / lipase Stool fat content Pancreatic function test CT scan Calcification Pseudocyst Dilation of main pancreatic duct Predisposes to pancreatic cancer Pancreatic carcinoma Epigastric - - + + - - - - N ↑ Alkaline phosphatase ↑ serum bilirubin ↑ gamma-glutamyl transpeptidase ↑ CA 19-9  MDCT with  PET/CT MRI Skin manifestations may include: Bullous pemphigoid Cicatricial pemphigoid Migratory superficial thrombophlebitis (classic Trousseau's syndrome) Pancreatic panniculitis Primary biliary cirrhosis RUQ/Epigastric − − + − + in late presentation − − − N Increased AMA level, abnormal LFTs Primary sclerosing cholangitis RUQ + − + − − − − − N Increased liver enzymes Increased IgM, IgG4 Anti-neutrophil cytoplasmic antibody (p-ANCA) Anti-nuclear antibody (ANA) Anti-smooth muscle antibody (Anti-Sm) Anti-endothelial antibody Anti-cardiolipin antibody ERCP and MRCP shows Multiple segmental strictures Mural irregularities Biliary dilatation and diverticula Distortion of biliary tree The risk of cholangiocarcinoma in patients with primary sclerosing cholangitis is 400 times higher than the risk in the general population. Cholelithiasis RUQ/Epigastric ± − ± − − − − − N to hyperactive for dislodged stone Leukocytosis Ultrasound shows gallstone Fatty food intolerance Gastric causes Peptic ulcer disease Diffuse ± − − − Gastric ulcer- melena and hematemesis Duodenal ulcer- melena and hematochezia + in perforated + + N Ascitic fluid LDH > serum LDH Glucose < 50mg/dl Total protein > 1g/dl Air under diaphragm in upright CXR Upper GI endoscopy for diagnosis Gastritis Epigastric ± − − − + in chronic gastritis − − − N H.pylori infection diagnostic tests Endoscopy H.pylori gastritis guideline recommendation Gastroesophageal reflux disease Epigastric − − − − − − − − N Esophageal manometry Gastric emptying studies Endoscopy for alarm signs Gastric outlet obstruction Epigastric − − − − − − − − Hyperactive Complete blood count Basic metabolic panel Abdominal x-ray- air fluid level Barium upper GI studies- narrowed pylorus Succussion splash Gastroparesis Epigastric - - - - - ± - - Hyperactive/hypoactive Hemoglobin Fasting plasma glucose Serum total protein, albumin, thyrotropin (TSH), and an antinuclear antibody (ANA) titer HbA1c Scintigraphic gastric emptying Succussion splash Single photon emission computed tomography (SPECT) Full thickness gastric and small intestinal biopsy Gastrointestinal perforation Diffuse + ± ± − +, depends on site + + ± Hyperactive/hypoactive WBC> 10,000 Air under diaphragm in upright CXR Hamman's sign Dumping syndrome Lower and then diffuse − − − + − + − − Hyperactive Glucose challenge test Hydrogen breath test Upper GI series Gastric emptying study Postgastrectomy Intestinal causes Acute appendicitis Starts in epigastrium, migrates to RLQ + +in pyogenic appendicitis − − − + in perforated appendicitis + + Hypoactive Leukocytosis Ultrasound shows evidence of inflammation Nausea & vomiting, decreased appetite Acute diverticulitis LLQ + ± − ± Hematochezia + in perforated diverticulitis + + Hypoactive Leukocytosis CT scan and ultrasound shows evidence of inflammation History of constipation Inflammatory bowel disease Diffuse ± − ± ± Hematochezia − − − N/ Hyperactive Anti-neutrophil cytoplasmic antibody (P-ANCA) in Ulcerative colitis Anti saccharomyces cerevisiae antibodies (ASCA) in Crohn's disease String sign on abdominal x-ray in Crohn's disease Extra intestinal findings: Uveitis Arthritis Irritable bowel syndrome Diffuse ± − − + − − − − N Tests done to exclude other diseases as it diagnosis of exclusion Tests done to exclude other diseases as it diagnosis of exclusion Symptomatic treatment High dietary fiber Osmotic laxatives Antispasmodic drugs Whipple's disease Diffuse ± − ± + − ± − − N Thrombocytopenia Hypoalbuminemia Small intestinal biopsy for Tropheryma whipplei Endoscopy is used to confirm diagnosis. Images used to find complications Chest and joint x-ray CT MRI Echocardiography Extra intestinal findings: Uveitis Endocarditis Encephalitis Dementia Hepatosplenomegaly Arthritis Ascites Toxic megacolon Diffuse + − − + − + ± − Hypoactive Anemia Leukocytosis especially in patients with Clostridium difficile infection Hypoalbuminemia Metabolic alkalosis associated with a poor prognosis Metabolic acidosis secondary to ischemic colitis CT scan shows: Dilated transverse colon Loss of colonic haustrations Segmental parietal thinning Intraluminal soft-tissue masses Ultrasound shows: Loss of haustra coli of the colon Hypoechoic and thickened bowel walls with irregular internal margins in the sigmoid and descending colon Prominent dilation of the transverse colon (>6 cm) Insignificant dilation of ileal bowel loops (diameter >18 mm) with increased intraluminal gas and fluid Tropical sprue Diffuse + − − + − − − − N Fat soluble vitamin deficiency Hypoalbuminemia Fecal stool test Barium studies show dilation and edema of mucosal folds Steatorrhea- 10-40 g/day (Normal=5 g/day) Celiac disease Diffuse − − − + − − − − Hyperactive IgA endomysial antibody IgA tissue transglutaminase antibody Anti-gliadin antibody Small bowel biopsy USG Bull’s eye or target pattern Pseudokidney sign Gluten allergy Infective colitis Diffuse + − − + Hematochezia + in fulminant colitis ± ± Hyperactive Stool culture and studies Shiga toxin in bloody diarrhea PCR CT scan Bowel wall thickening Edema Colon carcinoma Diffuse/localized - - - ± + ± - - Normal Hyperactive if obstruction present CBC Carcinoembryonic antigen (CEA) Colonoscopy Flexible sigmoidoscopy Barium enema CT colonography  PILLCAM 2: A colon capsule for CRC screening may be used in patients with an incomplete colonoscopy who lacks obstruction Hepatic causes Viral hepatitis RUQ + − + + in Hep A and E − + in fulminant hepatitis +in acute + N Abnormal LFTs Viral serology USG Hep A and E have fecoral route of transmission and Hep B and C transmits via blood transfusion and sexual contact. Liver masses RUQ + + in Liver abscess ± − + in Hepatocellular carcinoma + in sepsis + in Liver abscess + in Liver abscess N CBC LFTs USG Liver abscess RUQ + + + ± - + + ± Normal/hypoactive CBC Blood cultures Abnormal liver function tests US CT Hepatocellular carcinoma/Metastasis RUQ + - + - - - - - Normal Hyperactive if obstruction present High levels of AFP in serum Abnormal liver function tests US CT Liver biopsy Other symptoms: Splenomegaly Variceal bleeding Ascites Spider nevi Asterixis Budd-Chiari syndrome RUQ ± − ± − + in liver failure leading to varices − − − N Elevated serum aspartate aminotransferase and alanine aminotransferase levels may be more than five times the upper limit of the normal range. Elevated serum alkaline phosphatase and bilirubin levels, decreased serum albumin level. Findings on CT scan suggestive of Budd-Chiari syndrome include: Early enhancement of the caudate lobe and central liver around the inferior vena cava Delayed enhancement of the peripheral liver with accompanying central low density (flip-flop appearance) Peripheral zones of the liver show reversed portal venous blood flow In the chronic phase, there is caudate lobe enlargement and atrophy of the peripheral liver in affected areas Ascitic fluid examination shows: Total protein more than 2.5 g per deciliter White blood cells are usually less than 500/μL. Hemochromatosis RUQ − − − − + in cirrhotic patients − − − N >60% TS >240 μg/L SF Raised LFT Hyperglycemia Ultrasound shows evidence of cirrhosis Extra intestinal findings: Hyperpigmentation Diabetes mellitus Arthralgia Impotence in males Cardiomyopathy Atherosclerosis Hypopituitarism Hypothyroidism Extrahepatic cancer Prone to specific infections Cirrhosis RUQ − − + − varices + − − N Hypoalbuminemia Prolonged PT Abnormal LFTs Hyponatremia Thrombocytopenia USG Nodular, shrunken liver Ascites Stigmata of liver disease Cruveilhier- Baumgarten murmur Peritoneal causes Spontaneous bacterial peritonitis Diffuse + + + in cirrhotic patients + − ± + + Hypoactive Ascitic fluid PMN>250 cells/mm³ Culture: Positive for single organism Ultrasound for evaluation of liver cirrhosis Renal causes Pyelonephritis Lumbar region + ± - - - + ± ± Hypoactive Urinalysis Urine culture Blood culture CT MRI Renal punch positive Renal colic Flank pain − − − − − − − − N Hematuria CT scan and ultrasound Colicky abdominal pain Dysuria Hollow Viscous Obstruction Small intestine obstruction Diffuse + − − − − + + ± Hyperactive then absent Leukocytosis with left shift indicates complications Abdominal X ray dilated loops of bowel with air fluid levels gasless abdonen "Target sign"– , indicative of intussusception Venous cut-off sign" – suggests thrombosis Volvulus Diffuse +in perforated cases − − − − +in perforated cases + + Hyperactive then absent Leukocytosis CT scan and abdominal X ray U shaped sigmoid colon "Whirl sign" Biliary colic RUQ − − + − − − − − N Increased bilirubin and alkaline phosphatase Ultrasound Nausea & vomiting Vascular Disorders Ischemic causes Mesenteric ischemia Periumbilical + if bowel becomes gangrenous − − + Hematochezia + if bowel becomes gangrenous + if bowel becomes gangrenous − Hyperactive to absent Leukocytosis and lactic acidosis Amylase levels D-dimer CT angiography SMA or SMV thrombosis Also known as abdominal angina, worsens with eating Acute ischemic colitis Diffuse + ± − + Massive + + + Hyperactive then absent Leukocytosis Abdominal x-ray Distension and pneumatosis CT scan Double halo appearance, thumbprinting Thickening of bowel Can lead to shock Hemorrhagic causes Ruptured abdominal aortic aneurysm Diffuse ± − − − Herald to massive + − − N Fibrinogen D-dimer Focused Assessment with Sonography in Trauma (FAST)  Unstable hemodynamics Intra-abdominal or retroperitoneal hemorrhage Diffuse ± − − − Massive + − − N Anemia CT scan History of trauma Gynaecological Causes Tubal causes Torsion of the cyst RLQ / LLQ − − − − − − ± ± N Increased ESR and CRP Ultrasound Sudden onset & severe pain with nausea and vomiting Acute salpingitis RLQ / LLQ + ± − − − − ± ± N Leukocytosis Pelvic ultrasound Vaginal discharge Cyst rupture RLQ / LLQ − − − − − + ± ± N Increased ESR and CRP Ultrasound Sudden onset sever pain with nausea and vomiting Pregnancy Ruptured ectopic pregnancy RLQ / LLQ − − − − − + + + N Positive pregnancy test Ultrasound History of missed period and vaginal bleeding Extra-abdominal causes Pulmonary disorders Pleural empyema RUQ/Epigastric + ± − − − − − − N Thoracentesis Chest X-ray Pleural opacity USG Localization of effusion Physical examination Crackles Egophony Increased tactile fremitus Pulmonary embolism RUQ/LUQ ± - - - - ± - - N ABGs D-dimer CXR V/Q scan Spiral CT pulmonary angiogram Pneumonia RUQ/LUQ + + - - - + - - N/Hypoactive ABGs Eosinophilia Pancytopenia CXR CT chest Bronchoscopy Cardiovascular disorders Myocardial Infarction Epigastric − − − − − + in cardiogenic shock − − N ECG Cardiac enzymes Echocardiogram Wall motion abnormality Wall rupture Septal rupture Complications: Arrythmias Mitral regurgitation Ventricular wall rupture Septal rupture

RUQ= Right upper quadrant of the abdomen, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CT= Computed tomography

Disease History and clinical manifestations Diagnosis Lab Findings Other blood tests Other diagnostic AST ALT ALK BLR Indirect BLR Direct Viral serology Type of jaundice Pruritis Family history Common bile duct stone Cholestatic Jaundice + -/+ N N ↑ N ↑ - Dilated ducts on sono CT/ERCP Hepatitis A cholestatic type + - N N ↑ N ↑ + HAV- AB Abdominal ultrasound EBV / CMV hepatitis + - N N ↑ N ↑ + Positive serology PCR or ELISA Primary biliary cirrhosis + -/+ N/↑ N/↑ ↑ N ↑ - AMA positive Liver biopsy Primary sclerosing cholangitis + -/+ N/↑ N/↑ ↑ N ↑ - Beading on MRCP Liver biopsy Autoimmune hepatitis Hepatocellular Jaundice -/+ -/+ ↑ ↑ N ↑/N N - Anti-LKM antibody Liver biopsy

Disease History and clinical manifestations Diagnosis Lab Findings Other blood tests Other diagnostic AST ALT ALK BLR Indirect BLR Direct Viral serology Type of jaundice Pruritis RUQ pain Fever Family history Common bile duct stone Cholestatic Jaundice + + - -/+ N N ↑ N ↑ - Dilated ducts on sono CT/ERCP Hepatitis A cholestatic type + + -/+ - N N ↑ N ↑ + HAV- AB Abdominal ultrasound EBV / CMV hepatitis + + -/+ - N N ↑ N ↑ + Positive serology PCR or ELISA Primary biliary cirrhosis + -/+ - -/+ N/↑ N/↑ ↑ N ↑ - AMA positive Liver biopsy Primary sclerosing cholangitis + -/+ - -/+ N/↑ N/↑ ↑ N ↑ - Beading on MRCP Liver biopsy

Disease	Signs and Symptoms								Barium esophagogram	Endoscopy	Other imaging and laboratory findings	Gold Standard
	Onset	Dysphagia			Weight loss	Heartburn	Other findings	Mental status
		Solids	Liquids	Type
Plummer-Vinson syndrome	Gradual	+	-	Non progressive	+/-	-	Glossitis Koilonychia	Normal	Thin projections on the anterior esophageal wall Multiple upperesophageal constrictions	Direct visualization of esophageal webs Superior to esophagogram	Videofluoroscopy shows mucosal and submucosal foldings	Triad of Iron deficiency anemia Esophageal webs Glossitis
Esophageal stricture	Gradual Sudden onset	+	+/-	Progressive	+/-	+/-	Odynophagia Cough Chest pain	Normal	Sacculations Fixed transverse folds Esophageal intramural pseudodiverticula	Mucosal edema Circumferential thickening in GERD Pale mucosa with white exudate in lymphocytic esophagitis Swelling and hemorrhagic congestion in causticingestion	Manometry may show dysmotility CT scan for staging malignant strictures	No gold standard test Diagnostic study based on history of dysphagia, positive barium esophagogram and endoscopy
Diffuse esophageal spasm	Sudden	+	+	Non progressive	+	+	Chest pain	Normal	Nonperistaltic and nonpropulsive contractions Corkscrew or rosary bead esophagus	Inconclusive	Manometry shows high-amplitude esophageal contractions CT scan may show hypertrophy of esophageal muscles	Manometry
Achalasia	Gradual	+	+	Non progressive	+/-	-	Regurgitation of undigested food Chest pain	Normal	"Bird's beak" or "rat tail" appearance Dilated esophageal body Air fluid level (absent peristalsis) Absence of an intragastric air bubble	Dilated esophagus Residual food fragments Normal mucosa	Residual pressure of LES > 10 mmHg Incomplete relaxation of the LES Increased resting tone of LES Aperistalsis	History of dysphagia with positive endoscopy and manometry
Systemic sclerosis	Gradual	+	+	Progressive	+/-	+	Muscle and joint pain Raynaud's phenomenon Skin changes	Normal	Dysmotility Patulous esophagus	Mucosal damage Peptic stricture (advanced cases)	Positive serology for Antinuclear antibodies Rheumatoid factor Creatine kinase ESR	Skin biopsy
Zenker's diverticulum	Gradual	+	-		+/-	-	Food regurgitation Halitosis Cough Hoarseness	Normal	Thin projections on esophageal wall over Killian's triangle	Outpouching of posterior pharyngeal wall Exclude the presence of SCC	CT & MRI shows out-pouching over the posterior esophagus in the Killian's triangle	Barium esophagography
Esophageal carcinoma	Gradual	+	+	Progressive	+	+/-	Lymphadenopathy Cachexia	Normal	Irregular stricture Pre-stricture dilatation	Esophageal obstruction Staging of disease	CT and PET scan is an optional test for staging of the disease	Biopsy
Stroke (Cerebral hemorrhage)	Sudden	+	+	Progressive	+	+/-	Dysarthria Limb weakness Fatigue	Impaired	Pooling of contrast in the pharynx Aspiration of barium contrast into the airway	Reduced opening of upper esophageal sphincter Reduced larynx elevation	CT without contrast shows acute hemorrhage as a hyperattenuating clot	CT without contrast
Motor disorders (Myasthenia gravis)	Gradual	+	+	Progressive	+/-		Ptosis Diplopia Fatigue	Normal	Stasis in pharynx and pooling in pharyngeal recesses	Velopharyngeal insufficiency Delayed swallowing function	CT may show anterior mediastinal mass (thymoma) Positive tensilon test	Anti–acetylcholine receptor antibody test
GERD	Gradual Sudden onset	+	-	Progressive	+/-	+	Cough Hoarseness	Normal	Free acid reflux Esophagitis with scarring Strictures Barrett's oesophagus	Erythema, erosions and ulceration Barrett's esophagus	Esophageal manometry may show decreased tone of LES	24 hour esophageal pH monitoring
Esophageal web	Gradual	+	+/-	Progressive	-	+/-	Findings of the underlying cause such as iron deficiency anemia or bullous pemphigoid	Normal	Symmetrical narrowing of the esophagus	Smooth membrane not encircling the whole lumen	Videofluoroscopy shows mucosal and submucosal foldings	Barium esophagogram
Eosinophilic esophagitis

polyglandular autoimmune syndrome polyendocrine autoimmune syndrome

tryptophan hydroxylase presenting with malabsorption

• • • Tyrosine hydroxylase presenting with alopecia areata
    • Liver presenting with autoimmune liver disease and chronic active hepatitis
    • Steroidal hormone–producing cell presenting with hypogonadism.

X linked polyendocrinopathy, immune dysfunction and diarrhea. This condition is very rare and generally presents in neonatal period with diabetes and malabsorption. Unlike type 1 and type 2 autoimmune polyglandular syndromes there is no association with HLA genotype. Mutation in FOXP3 gene is inherited as X linked and leads to loss of regulatory T cells and autoimmunity.

The term “polyendocrine” itself is a misnomer, in that not all patients have multiple endocrine disorders, and many have nonendocrine autoimmune diseases. Nevertheless, the recognition that patients in whom multiple autoimmune disorders are diagnosed may have a specific genetic syndrome, may be at increased risk for multiple autoimmune disorders, and may have relatives who have an increased risk should spur clinicians toward early diagnosis and treatment.

In the simplest hypothesis for understanding organ-specific autoimmunity, the initial step is the loss of immunologic tolerance to a peptide within a specific molecule found in the target organ. Clones of the CD4 T cells that recognize the peptide then expand, and the specific cytokines produced by the clonal CD4 T cells favor inflammation (as when type 1 helper T [Th1]–cell clones produce cytokines such as interferon-γ) or favor autoantibody-mediated disease (as is the case predominantly with type 2 helper T [Th2]–cell clones).9 The probability of T-cell autoreactivity is determined both in the thymus (the site of central tolerance) and in the periphery (the site of peripheral tolerance) and is strongly influenced by specific HLA alleles

TYPE 1 APS Mutations in the AIRE gene cause many autoimmune diseases, and affected patients are at risk for the development of multiple additional autoimmune diseases over time, including type 1A diabetes, hypothyroidism, pernicious anemia, alopecia, vitiligo, hepatitis, ovarian atrophy, and keratitis. Affected patients may also have diarrhea or obstipation that may be related to the destruction of gastrointestinal endocrine cells (enterochromaffin and enterochromaffin-like cells).39 Knockout of the AIRE gene in the mouse produces widespread autoimmunity, but the phenotype is relatively mild. SYMPTOMS TYPE1 Addison's disease develops in 80 percent of patients with autoimmune polyendocrine syndrome type I, and type 1A diabetes develops in 18 percent

PROGNOSISI TYPE 1 After diagnosis, patients with autoimmune polyendocrine syndrome type I require close monitoring. Monitoring can help prevent illness associated with delayed diagnosis of additional autoimmune diseases (e.g., Addison's disease and hypoparathyroidism, which can develop during adulthood) as well as oral cancer, which may develop if candidiasis is not treated aggressively, and infection due to asplenism, which is present in a subgroup of patients.

• In patients with autoimmune polyendocrine syndromes who have a single disorder such as Addison's disease or type 1A diabetes, the prevalence of additional autoimmune disorders is 30 to 50 times that in the general population.60,61 The concurrence of more than one endocrinopathy presumably results from shared genetic susceptibility leading to loss of tolerance to multiple tissues

TYPE 2 Autoimmune polyendocrine syndrome type II (also called Schmidt's syndrome with Addison's disease plus hypothyroidism) is much more common and more varied in its manifestations than autoimmune polyendocrine syndrome type I.

TYpe 3 X-Linked Polyendocrinopathy, Immune Dysfunction, and Diarrhea. The syndrome of X-linked polyendocrinopathy, immune dysfunction, and diarrhea (known as XPID) is an extremely rare disorder characterized by fulminant, widespread autoimmunity and type 1A diabetes, which usually develops in neonates; it is often fatal. The disorder is also known as XLAAD (X-linked autoimmunity and allergic dysregulation) and IPEX (immune dysfunction, polyendocrinopathy, and enteropathy, X-linked)

Aldosterone Deficiency: Hyporeninemic hypoaldosteronism - Commonly seen in patients with renal insufficiency (diabetic kidney disease, chronic tubulointerstitial disease, or glomerulonephritis) and those that take certain medications (non-steroidal anti-inflammatory drugs, calcineurin inhibitors).[1] Angiotensin inhibitors - angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), direct renin inhibitors Heparin therapy (including low molecular weight heparin) - Heparin has a direct toxic effect on the adrenal zona glomerulosa cells which leads to a reduction in plasma aldosterone concentration.[9] Primary adrenal insufficiency (Addison’s disease) - Associated with the lack of cortisol and aldosterone. This can result from autoimmune adrenalitis, infectious adrenalitis, and other disorders.[14] Critical illness - There is decreased adrenal production of aldosterone and stress-induced hypersecretion of ACTH which can diminish aldosterone synthesis by diverting substrate to the production of cortisol. Congenital isolated hypoaldosteronism - Deficiency of enzymes required for aldosterone synthesis.[14] Pseudohypoaldosteronism type 2 (Gordon’s syndrome or familial hyperkalemic hypertension) - Abnormalities in WNK kinases in the distal nephron increase chloride reabsorption leading to reduced renal potassium secretion. Characterized by hypertension, hyperkalemia, metabolic acidosis, normal renal function, and low or low-normal plasma renin activity and aldosterone concentrations.[14][2] Aldosterone Resistance: Inhibitors of the epithelial sodium channel - Most commonly associated with the administation of potassium-sparing diuretics (spironolactone, eplerenone, amiloride) and certain antibiotics (trimethoprim, pentamidine). Pseudohypoaldosteronism type 1 - Characterized by marked elevations of plasma aldosterone levels. There is an autosomal recessive form, and an autosomal dominant or sporadic form. The autosomal dominant form tends to be associated with milder symptoms

Type of Adrenal insufficiency	Skin Pigmentation	ACTH	Normal ACTH
Addison disease	+	>60 ng/mL	5-30 ng/mL
Secondary / tertiary adrenal insufficiency	-	<5 ng/mL

Addison's disease must be differentiated from other diseases that cause hypotension, skin pigmentation, and abdominal pain such as myopathies, celiac disease, Peutz-Jeghers syndrome ,anorexia nervosa, syndrome of inappropriate anti-diuretic hormone (SIADH), neurofibromatosis, porphyria cutanea tarda, salt-depletion nephritis and bronchogenic carcinoma.

Disease	Differentiating symptoms							Differentiating laboratory findings			Gold standard test
	Hypotension	Abdominal pain	Anorexia/ weight loss	Muscle weakness	Hypoglycemia	Skin pigmentation	Other symptoms	Hyponatremia	Cortisol levels	Other labs
Addison's disease	+	+	+	+	+	+		-	Low		ACTH stimulation test
Myopathies (polymyositis, hereditary myopathies)	-	-	-	+	-	Heliotrope rash and Gottron's sign	Muscle tenderness	-	Normal	-	Muscle biopsy
Celiac disease	-	+	+	-	-	Dermatitis herpetiformis	Greasy stools Increased fecal fat	-	Normal	-	Abnormal small bowel biopsy
Syndrome of inappropriate anti-diuretic hormone (SIADH)	-	-	-	-	-	-	-	+	Normal	Decreased osmolality Euvolemia Sodium in urine typically >20 mEq/L	Water deprivation test
Neurofibromatosis	-	-	+	+	-	Axillary- and inguinal-area freckling	Occasional development of peripheral sarcomas May have overgrowth of subcutaneous tissues	-	-	-	Biopsy of skin tissue
Peutz-Jeghers syndrome		+				+	Melanotic hyperpigmentation of the skin and mucous membranes	-	Normal		Colonic imaging showing the small intestinal polyps
Porphyria cutanea tarda	-	+	-	-	-	Blisters on sun-exposed sites	Associated liver disease (usually hepatitis C) Hypertrichosis	-	Normal or elevated	High level of porphyrins in the urine
Salt-depletion nephritis	+	Flank pain	-	-	-	-	Fever Dysuria Pyuria Oliguria	+	Elevated	<15:1 BUN:CR
Bronchogenic carcinoma	-	-	+	-	-	+	Cough Dyspnea Hemoptysis	-	Elevated	Increased ACTH and Hypokalemia	Cytological or histological evidence of lung cancer in sputum, pleural fluid, or tissue
Anorexia nervosa	+	-	+	+	+	-	Distorted body image Oligomenorrhea	-	Elevated	-	Psychiatric condition