NAFLD vs. NASH

Nonalcoholic fatty liver disease (NAFLD) affects over 1/4th of the world’s population. It has become the leading cause of cirrhosis in developed western countries. NAFLD and NASH exist along a spectrum. 

NAFLD: Patients are usually asymptomatic and the condition is found incidentally. It is defined as:  >5% of hepatic steatosis in patients who do not consume excessive alcohol. They will not have hepatocellular injury (∼80% of patients have normal-range ALT levels).

Approximately 10–30% will progress to non-alcoholic steatohepatitis (NASH). Which is differentiated by inflammation and hepatocellular injury (elevated ALT>AST). Its the active form of NAFLD, with hepatic necro-inflammation and faster fibrosis progression.

Image Credit: Nature.com

REFERENCES

1) Dyson JK, Anstee QM, McPherson S. Non-alcoholic fatty liver disease: a practical approach to diagnosis and staging. Frontline Gastroenterology 2014;5:211-218.

2) Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018 Jan;67(1):328-357. doi: 10.1002/hep.29367. Epub 2017 Sep 29. 

Hepatopulmonary syndrome vs. Portopulmonary hypertension

Often confused as the same syndrome, Hepatopulmonary syndrome and Portopulmonary hypertension are two distinct disease processes. Both are characterized as pulmonary vascular abnormalities in the context of liver disease.

 

Hepatopulmonary Syndrome (HPS): triad of vasodilatation (Intrapulmonary vascular dilatations), abnormal oxygenation (an elevated alveolar-arterial oxygen gradient) and liver disease (any degree of liver disease). *LOOK FOR: digital clubbing, cyanosis and spider angiomas.

 

Portopulmonary hypertension (POPH): vascular obstruction secondary to portal hypertension (varices, splenomegaly, thrombocytopenia, portal vein abnormalities) with concomitant pulmonary arterial hypertension (mean pulmonary artery pressure >25 mmHg at rest, mean pulmonary capillary wedge pressure <15 mmHg, and pulmonary vascular resistance (PVR) >3 Wood units.

 

REFERENCES:

1. Porres-Aguilar M, Altamirano JT, Torre-Delgadillo A, Charlton MR, Duarte-Rojo A. Portopulmonary hypertension and hepatopulmonary syndrome: a clinician-oriented overview. Eur Respir Rev. 2012 Sep 1;21(125):223-33. doi: 10.1183/09059180.00007211.

2. Gupta S, Krowka M J. Hepatopulmonary syndrome. CMAJ Feb 2018, 190 (8) E223; DOI: 10.1503/cmaj.170253

Why Prednisolone for Alcoholic Hepatitis?

Patients presenting with severe alcoholic hepatitis (Discriminant Function value ≥32) have high short-term mortality and may benefit from treatment with glucocorticoids.

Prednisolone is used as oppose to prednisone for 28 days (with taper).

 

WHY? Prednisone requires conversion to prednisolone (the active metabolite) in the liver. This process may be impaired in alcoholic hepatitis.

 

REFERENCES

  1.  Ramond MJ, Poynard T, Rueff B, Mathurin P, Theodore C, Chaput JC, Benhamou JP. A randomized trial of prednisolone in patients with severe alcoholic hepatitis. N Engl J Med 1992; 326:507. 
  2. Friedman SL, McQuaid KR, Grendell JH, et al. Current Diagnosis & Treatment in Gastroenterology, 2nd ed, McGraw-Hill Medical 2002.

Factor VIII: DIC vs Liver Disease (Cirrhosis)

Distinguishing between the coagulation abnormalities of liver disease vs. Disseminated intravascular coagulation (DIC) can be difficult as clinical and biochemical findings are similar.

However, Factor VIII levels are usually increased or normal in liver disease. 

Whereas, Factor VIII levels are decreased in DIC.

WHY? Factor VIII is produced in endothelial cells rather than the liver; hence it is not affected by the process of cirrhosis.

REFERENCES

  1. Senzolo M, Burra P, Cholongitas E, Burroughs AK. New insights into the coagulopathy of liver disease and liver transplantation. World J Gastroenterol. 2006;12(48):7725-36.
  2. Mammen EF. Coagulation abnormalities in liver disease. Hematol Oncol Clin North Am. 1992 Dec;6(6):1247-57.

Why does Alpha-1 Antitrypsin Deficiency cause Cirrhosis?

Alpha-1 antitrypsin is an anti protease that protects the lungs from endogenous elastases, collagenases, and protease. These enzymes are responsible for the break down of proteins.

In smoking patients with early onset liver disease or panlobular emphysema, the diagnosis of  alpha-1 antitrypsin deficiency should be considered.

Why does it cause cirrhosis?

The cirrhosis results from the inability to release the mutated alpha-1 antitrypsin protein which is made in the liver. It accumulates in the liver and results in cellular death and necrosis.

REFERENCES

  1. Laboratory Medicine: The Diagnosis of Disease in the Clinical Laboratory. William E. Winter. Chapter 16: The Liver and Biliary Tract.
  2. Stoller JK, Aboussouan LS. A review of α1-antitrypsin deficiency. Am J Respir Crit Care Med. 2012 Feb 1;185(3):246-59. doi: 10.1164/rccm.201108-1428CI.

Compensated vs. Decompensated Cirrhosis

Compensated: Patients with cirrhosis that have not developed major complications of cirrhosis.

Img Cred: Sciencedirect.com

Decompensated: Patients with cirrhosis who have developed major complications:

  • Variceal hemorrhage
  • Ascites
  • Hepatic encephalopathy
  • Spontaneous bacterial peritonitis
  • Hepatocellular carcinoma
  • Hepatorenal syndrome

REFERENCES

  • D’Amico, G. Garcia-Tsao, L. Pagliaro Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol, 44 (2006), pp. 217-231

Why 2:1 Ratio of AST/ALT in Alcoholic Hepatitis?

Alcoholic hepatitis lab findings classically reveal serum AST/ ALT >2. (Although rarely above 300 IU per milliliter). Although this finding is neither specific nor sensitive.

WHY??? The proposed mechanisms accounting for this high ratio are reduced hepatic alanine aminotransferase activity, alcohol-induced depletion of hepatic pyridoxal 5′-phosphate (B6), and increased hepatic mitochondrial aspartate.

REFERENCES

  1. Vech RL, Lumeng L, Li TK. VitaminB6 metabolism in chronic alcohol abuse:the effect of ethanol oxidation on hepaticpyridoxal 5′-phosphate metabolism. J ClinInvest 1975;55:1026-32.
  2. Matloff DS, Selinger MJ, Kaplan MM. Hepatic transaminase activity in alcoholic liver disease. Gastroenterology 1980;78: 1389-92.
  3. Cohen JA, Kaplan MM. The SGOT/SGPT ratio — an indicator of alcoholic liver disease. Dig Dis Sci 1979;24:835-8.

Indications for SBP Prophylaxis

Antibiotic prophylaxis for patients with risk factors for spontaneous bacterial peritonitis (SBP) include:

  • Known history of SBP: Typically prolonged outpatient fluoroquinolone or TMP-SMX
  • Cirrhotic patients with GI bleed: Ceftriaxone 1q q24hrs [short-term]
  • Patients found to have ascites with ascitic total protein concentration <1.5g/dL or 15g/L [2,3,4]: Typically prolonged outpatient fluoroquinolone or TMP-SMX

REFERENCES

  1. Alaniz C, Regal RE. Spontaneous Bacterial Peritonitis: A Review of Treatment Options. Pharmacy and Therapeutics. 2009;34(4):204-210.
  2. Fernandez J, Navasa M, Planas R, et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology 2007;133:818–824.74. 
  3. Terg R, Fassio E, Guevara M, et al. Ciprofloxacin in primary prophylaxis of spontaneous bacterial peritonitis: A randomized,placebo-controlled study. J Hepatol 2008;48:774–779.
  4. Llach J, Rimola A, Navasa M, et al. Incidence and predictivefactors of first episode of spontaneous bacterial peritonitis in cirrhosis with ascites: Relevance of ascitic fluid protein concentration. Hepatology. 1992;16:724–727.

Proton Pump Inhibitors for Upper GI Bleed: Mechanism

During the bleed, there will be sympathetic mediated vasoconstriction and also hemostasis (platelet plug).

It has been demonstrated in an acidic environment (6.0 compared physiological pH 7.4), there is a 2-4 fold prolongation of prothrombin time, aPTT, and thrombin time.

Thus, in an acidic environment, the coagulation cascade and platelet aggregation are inhibited and disaggregation of stable platelet plugs occurs.

In addition, pepsinogen is converted to pepsin under acidic conditions. Pepsin can lyse the blood clots that plug vessels in the ulcer base and induce re-bleeding thereafter.

REFERENCES

  1. Green F., Kaplan M., Curtis L., Levine P.. Effect of acid and pepsin on blood coagulation and platelet aggregation. A possible contributor prolonged gastroduodenal mucosal hemorrhage. Gastroenterology. 1978;74:38–43.
  2. Low J., Dodds A., Biggs J. Fibrinolytic activity of gastroduodenal secretions–a possible role in upper gastrointestinal haemorrhage. Thromb Res. 1980;17:819–830
  3. Leontiadis GI, Sharma VK, Howden CW. Proton pump inhibitor treatment for acute peptic ulcer bleeding. Cochrane Database Syst Rev. 2006:CD002094.
  4. Lin HJ. Role of proton pump inhibitors in the management of peptic ulcer bleeding. World Journal of Gastrointestinal Pharmacology and Therapeutics. 2010;1(2):51-53. doi:10.4292/wjgpt.v1.i2.51.
  5. Lau JY, Sung JJ, Lee KK, Yung MY, Wong SK, Wu JC, Chan FK, Ng EK, You JH, Lee CW, et al. Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. N Engl J Med. 2000;B:310–316.

 

SSRI and Upper GI Bleed: Mechanism

SSRIs have been implicated in a modest increase risk of Upper GI bleeds in recent meta-analysis and review. [6]

Img Cred: bloodjournal.org
Img Cred: bloodjournal.org

PROPOSED MECHANISM: Platelets will release serotonin in response to vascular damage/ injury. This promotes the pro-thrombotic cascade promoting vasoconstriction and platelet aggregation. However, platelets do not create serotonin and rely on serotonin transporters (SERT).

SSRIs inhibit the serotonin transporter, which is responsible for the uptake of serotonin into platelets. It could thus be theorized that SSRIs would deplete platelet serotonin, leading to a reduced ability to form clots and a subsequent increase in the risk of bleeding.

REFERENCES

  1. Paton, C. SSRIs and gastrointestinal bleeding. BMJ. 2005;331:529
  2. Anglin R, Yuan Y, Moayyedi P, Tse F, Armstrong D, Leontiadis GI. Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis. Am J Gastroenterol. 2014 Jun;109(6):811-9. doi: 10.1038/ajg.2014.82. Epub 2014 Apr 29.
  3. Maurer-Spurej E. Serotonin reuptake inhibitors and cardiovascular diseases: a platelet connection. Cell Mol Life Sci. 2005;62(2):159-170.
  4. Gabriele Jedlitschky, Andreas Greinacher and Heyo K. Kroemer. Transporters in human platelets: physiologic function and impact for pharmacotherapy. Blood 2012 119:3394-3402; doi:10.1182/blood-2011-09-336933
  5. Opatrny L, Delaney JA, Suissa S . Gastro-intestinal haemorrhage risks of selective serotonin receptor antagonist therapy: a new look. Br J Clin Pharmacol. 2008;66(1):76.
  6. Anglin R, Yuan Y, Moayyedi P, Tse F, Armstrong D, Leontiadis GI.  Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis. Am J Gastroenterol. 2014;109(6):811.
  7. Loke YK, Trivedi AN, Singh S. Meta-analysis: gastrointestinal bleeding due to interaction between selective serotonin uptake inhibitors and non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther. 2008;27(1):31.