Why does my patient with alcoholic cirrhosis have macrocytic anemia?

Macrocytic anemia is commonly due to folate or vitamin B12 (cobalamin) deficiency.1 Deficiency in these vitamins can be related broadly to poor intake, poor absorption, or drug interference. In patients with chronic excess alcohol consumption, both intake and/or absorption of these vitamins may be affected.

Although folate deficiency is increasingly rare in many developed countries due to mandatory folate fortification of flour and uncooked-grain, alcohol use can be associated with malnourishment severe enough to causes folate deficiency. In addition, alcohol itself can alter folate metabolism and absorption.  More specifically, chronic alcohol consumption has been shown to be associated with decreased folate absorption by the small intestine, altered intrahepatic processing and distribution between the systemic and enterohepatic folate circulations as well as increased folate urinary excretion. 2 Though uncommon,3 alcohol can also be associated with a food B12 malabsorption process, whereby despite adequate intake, B12 is not released or absorbed from food. 4

But what if serum folate and B12 levels return as normal in our patient with macrocytosis? It turns out that alcohol consumption, independent of folate or B12 deficiency, may also cause macrocytosis. 5 Though the exact mechanism is unknown, it may be related to alcohol’s direct toxicity or that of its metabolites; alcohol is oxidized to acetaldehyde, which affects membranes of red blood cells (RBCs) and their precursors by forming adducts with erythroid proteins,6 and interfering with cell division.7 Interestingly, alcohol-related macrocytosis may appear before anemia is detected and can resolve within 2-4 months of abstinence.

In addition to alcohol, cirrhosis itself may be associated with macrocytic anemia caused by lipid deposition on RBC membranes.1

See also a related pearl at  https://pearls4peers.com/2019/07/26/my-patient-with-anemia-has-an-abnormally-high-mean-red-blood-cell-corpuscular-volume-mcv-what-conditions-should-i-routinely-consider-as-a-cause-of-his-macrocytic-anemia   

References

  1. Hoffbrand V, Provan D. ABC of clinical haematology: macrocytic anaemias. BMJ 2011;314(7078):430–430. https://www.ncbi.nlm.nih.gov/pubmed/9040391
  2. Medici V, Halsted CH. Folate, alcohol, and liver disease. Mol Nutr Food Res 2013;57(4):596–606. https://www.ncbi.nlm.nih.gov/pubmed/23136133
  3. Bode C, Bode CJ. Effect of alcohol consumption on the gut. Best Pract Res Clin Gastroenterol [Internet] 2003;17(4):575–92. https://www.sciencedirect.com/science/article/pii/S1521691803000349
  4. Dali-Youcef N, Andrès E. An update on cobalamin deficiency in adults. QJM 2009;102(1):17–28. https://academic.oup.com/qjmed/article/102/1/17/1502492
  5. Savage DG, Ogundipe A, Allen RH, Stabler SP, Lindenbaum J. Etiology and diagnostic Evaluation of macrocytosis. Am J Med Sci [Internet] 2000;319(6):343–52. http://dx.doi.org/10.1016/S0002-9629(15)40772-4 https://www.ncbi.nlm.nih.gov/pubmed/10875288
  6. Latvala J, Parkkila S, Melkko J, Niemelä O. Acetaldehyde adducts in blood and bone marrow of patients with ethanol-induced erythrocyte abnormalities. Mol Med 2001;7(6):401–5. https://www.ncbi.nlm.nih.gov/pubmed/11474133
  7. Wickramasinghe SN, Malik F. Acetaldehyde causes a prolongation of the doubling time and an increase in the modal volume of cells in culture. Alcohol Clin Exp Res 1986;10(3):350–4. https://www.ncbi.nlm.nih.gov/pubmed/3526962

 

Contributed by Kim Schaefer, Harvard medical student, Boston, MA

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Why does my patient with alcoholic cirrhosis have macrocytic anemia?

My patient with anemia has an abnormally high mean red blood cell corpuscular volume (MCV). What conditions should I routinely consider as a cause of his macrocytic anemia?

Anemia with mean corpuscular volume (MCV) above the upper limit of normal (usually ≥ 100 fL) is considered macrocytic anemia. The numerous causes of macrocytic anemia can be divided into major categories (1,2) (Figure 1).

First, a reticulocyte production index should be calculated and if elevated the MCV can be above the normal range due to the large size of reticulocytes. Once high MCV is not thought to be related to reticulocytosis, the majority of macrocytic anemias can be categorized according to one of two major mechanisms: 1. Liver disease; and  2. Impairment of DNA synthesis, which includes nutritional deficiencies (folate, B12), drug effect (e.g co-trimoxazole, anti-neoplastic agents and certain anti-retroviral drugs) and “idiopathic” causes (myelodysplastic syndromes).

Mild macrocytosis can also be seen in hypothyroidism and hypoproliferative anemias such as aplastic anemia.  Macrocytosis without anemia or liver disease can also be a manifestation of heavy alcohol intake.

Macrocytic anemia in liver disease is due to excess lipid deposition in the red blood cell (RBC) membrane, not impairment of DNA synthesis. Enlarged RBCs are usually round and  often have a targeted appearance in liver disease; acanthocytes (spur cells) may also be present (Fig 2). In contrast, in disorders of impaired DNA synthesis, enlarged RBCs are often oval-shaped (macro-ovalocytes) (Fig 3).

Other common abnormalities seen with macrocytic anemia include hypersegmented neutrophils (eg, induced by B12 or folate deficiency), and in the case of myelodysplastic syndromes, hypogranulated neutrophils and Pelger-Huet neutrophil abnormalities.

Bonus pearl: Did you know that the MCV unit, fL, stands for femtoliters or 1/1,000,000,000,000,000 L? 

macroalgo

Figure 1. Major causes of macrocytic anemia. MDS: myelodysplastic syndrome.

 

Macrocytic_Anemia_Figure 1

Fig 2. Round macrocytes with targeting and abundant acanthocytes (spur cells) in a patient with hepatic cirrhosis.

 

Macrocytic_Anemia_Figure 2

Fig 3. Oval macrocytes in a patient with large granular cell leukemia and an MCV of 125 fL who received cyclophosphamide.

References

  1. Ward PC. Investigation of Macrocytic Anemia. Postgrad Med 1979; 65: 203-207. https://www.ncbi.nlm.nih.gov/pubmed/368738
  2. Green R, Dwyre DM. Evaluation of macrocytic anemias. Semin Hematol 2015; 52: 279-286. https://www.sciencedirect.com/science/article/abs/pii/S0037196315000554

 

Contributed by Tom Spitzer, MD, Director of Cellular Therapy and Transplantation Laboratory, Massachusetts General Hospital, Boston, MA.

My patient with anemia has an abnormally high mean red blood cell corpuscular volume (MCV). What conditions should I routinely consider as a cause of his macrocytic anemia?

My patient with cocaine and alcohol addiction is admitted with repeated convulsions during which he seems totally conscious. What could I be missing?

Consider strychnine poisoning as a cause of recurrent generalized tonic clonic seizures and muscle spasm with clear sensorium either during or following the episode. 1-4 In contrast to the cortical source of most seizures, convulsions due to strychnine poisoning are due to the blocking of the action of spinal and brain-stem inhibitory neurons resulting in overwhelming muscle rigidity, not unlike that seen in tetanus.

Although strychnine was found in various tonics and cathartic agents and was a common cause of accidental death in children under 5 years of age in early 20th century, it is still used in various rodenticides and pesticides.3  Today, it may be used intentionally in suicide attempts as well as an adulterant in street drugs, such as amphetamines, heroin and especially cocaine. 1,3,5

The initial symptoms of strychnine poisoning include nervousness, a hyperalert state, and confusion. These symptoms may be followed by severe muscle rigidity throughout the body often in response to minimal stimuli, such as physical contact, bright lights, noise and medical procedures.3, 6,7  Interestingly, strychnine also has an excitatory action on the medulla and enhances the sensation of touch, smell, hearing and sight.6  The cause of death is usually respiratory arrest due to prolonged muscle spasms, often complicated by rhabdomyolysis and associated renal failure.1

So among the numerous causes of seizures, think of strychnine as another potential cause when there is no concurrent loss of consciousness or the expected postictal state.

Bonus Pearl: Did you know that strychnine may be present in street drugs with a variety of names such as “back breakers”, “homicide”, “red rock opium”, “red stuff” and “spike”? 7

 

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References

  1. Wood DM, Webser E, Martinez D, et al. Case report: survival after deliberate strychnine self-poisoning, with toxicokinetic data. Critical Care 2002;6:456-9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC130147/
  2. Santhosh GJ, Joseph W, Thomas M. Strychnine poisoning. J Assoc Physicians India 2003;51:736. https://www.ncbi.nlm.nih.gov/pubmed/14621058
  3. Libenson MH, Young JM. Case records of Massachusetts General Hospital. A 16 years boy with an altered mental status and muscle rigidity. N Engl J Med 2001;344:1232-9. https://www.nejm.org/doi/full/10.1056/NEJM200104193441608
  4. Smith BA. Strychnine poisoning. J Emerg Med 1990;8: 321-25. https://www.ncbi.nlm.nih.gov/pubmed/2197324
  5. O’Callaghan WG, Ward M, Lavelle P, et al. Unusual strychnine poisoning and its treatment: report of eight cases. B Med J 1982;285:478. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1499293/
  6. Burn DJ, Tomson CRV, Seviour J, et al. Strychnine poisoning as an unusual cause of convulsions. Postgrad Med J 1989;65:563-64. https://www.ncbi.nlm.nih.gov/pubmed/2602253
  7. Radosavljevic J, Jeffries WS, Peter JV. Intentional strychnine use and overdose—an entity of the past? Crit Care Resusc 2006;8: 260-61. https://www.ncbi.nlm.nih.gov/pubmed/16930120

 

My patient with cocaine and alcohol addiction is admitted with repeated convulsions during which he seems totally conscious. What could I be missing?

Why is my hospitalized patient with alcohol withdrawal syndrome so thrombocytopenic?

Although thrombocytopenia associated with chronic alcoholism may be related to complications of cirrhosis (eg, platelet sequestration in spleen due to portal hypertension, poor platelet production, and increased platelet destruction) (1), it may also occur in the absence of cirrhosis due to the direct toxic effect of alcohol on platelet production and survival (2).

 
In a prospective study of patients ingesting the equivalent of a fifth or more daily of 86 proof whiskey admitted for treatment of alcohol withdrawal—without evidence of severe liver disease, infection or sepsis— 81% had initial platelet counts below 150,000/µl, with about one-third having platelet counts below 100,000 µl (as low as 24,000/ul) (3).
In most patients, 2-3 days elapsed before the platelet count began to rise significantly, peaking 5-18 days after admission. Others have also reported that platelet counts rise within 5-7 days and normalize in a few weeks after alcohol withdrawal (1); bleeding complications have been uncommon in this setting.
Perhaps even more intriguing is the report of the association between thrombocytopenia in early alcohol withdrawal and the development of delirium tremens or seizures (sensitivity and specificity ~ 70%, positive predictive value less than 10% but with a negative predictive value of 99%) (4)! In fact, the authors suggested that, if their findings are corroborated, a normal platelet count could potentially be used to identify patients at low risk of alcohol withdrawal syndrome and therefore outpatient therapy. 

References
1. Mitchell O, Feldman D, Diakow M, et al. The pathophysiology of thrombocytopenia in chronic liver disease. Hepatic Medicine: Evidence and Research 2016;8 39-50. https://www.dovepress.com/the-pathophysiology-of-thrombocytopenia-in-chronic-liver-disease-peer-reviewed-article-HMER

2. Cowan DH. Effect of alcoholism on hemostasis. Semin Hematol 1980;17:137-47. https://www.ncbi.nlm.nih.gov/pubmed/6990498

3. Cowan DH, Hines JD. Thrombocytopenia of severe alcoholism. Ann Intern Med 1971;74:37-43. http://annals.org/aim/article-abstract/685069/thrombocytopenia-severe-alcoholism.

4. Berggren U, Falke C, Berglund KJ, et al. Thrombocytopenia in early alcohol withdrawal is associated with development of delirium tremens or seizures. Alcohol & Alcoholism 2009;44:382-86. https://www.ncbi.nlm.nih.gov/pubmed/19293148

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Why is my hospitalized patient with alcohol withdrawal syndrome so thrombocytopenic?

Should my patient with suspected alcoholic hepatitis undergo liver biopsy?

Although a characteristic clinical history and biochemical pattern of liver injury can strongly suggest the diagnosis of alcoholic hepatitis (AH), a definitive diagnosis is confirmed with liver biopsy only. In fact, in 30% of patients clinically diagnosed as having AH, a liver biopsy may lead to an alternative diagnosis.1Understandably, many physicians are reluctant to proceed with biopsy in this fragile patient population given the associated risks, notably bleeding. For this reason, most patients with AH are clinically diagnosed without a liver biopsy. However, there are certain instances in which a biopsy can be helpful, including when:2

  • Diagnosis of AH is in doubt
  • Suspicion for another disease process that may be contributing in parallel to AH is high
  • Obtaining prognostic data or identification of advanced hepatic fibrosis or cirrhosis in AH is desired

Thus, liver biopsy findings may influence short- and long-term management in AH. For these reasons, the European Association for the Study of the Liver recommends consideration of a liver biopsy in patients with AH.3 To minimize the bleeding risk, the transjugular approach is preferred.

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References

  1. Mookerjee RP, Lackner C, Stauber R, et al. The role of liver biopsy in the diagnosis and prognosis of patients with acute deterioration of alcoholic cirrhosis. J Hepatol 2011; 55:1103-1111 Link
  2. Altamirano J, Miquel R, Katoonizadeh A, et al. A histologic scoring system for prognosis of patients with alcoholic hepatitis. Gastroenterology 2014;146: 1231-1239. PDF
  3. European Association for the Study of Liver. EASL clinical practical guidelines: management of alcoholic liver disease. J Hepatol 2012; 57:399-420. PDF

Contributed by Jay Luther, MD, Gastrointestinal Unit, Mass General Hospital, Boston, MA.

Should my patient with suspected alcoholic hepatitis undergo liver biopsy?

Is it possible to have acute pancreatitis with normal serum lipase?

Yes! Although an elevated serum lipase has a negative predictive value of 94%-100% for acute pancreatitis (1), there are ample reports in the literature of patients with CT findings of pancreatitis in the presence of abdominal symptoms but with normal serum lipase and/or amylase (2,3).

A case series and review of literature of acute pancreatitis with normal lipase and amylase failed to reveal any specific risk factors for such observation (2). More specifically, the etiologies of acute pancreatitis in the reported cases have varied, including drug-induced, cholelithiasis, alcohol, hypertriglyceridemia, and postoperative causes.

But what accounts for this phenomenon? Many cases have been associated with the first bout of pancreatitis without evidence of pancreatic calcifications which makes the possibility of a “burned-out” pancreas without sufficient acinar cells to release lipase as a frequent cause unlikely. Other potential explanations for normal lipase in acute pancreatitis have included measurement of serum lipase at a very early phase of the disease before significant destruction of acinar cells has occurred (increases in 3-6 h, peaks at 24 h [4]) and more rapid renal clearance of serum lipase due to tubular dysfunction (2).

Of note, unlike amylase, lipase is totally reabsorbed by renal tubules under normal conditions (5). Thus, it’s conceivable that even a reversible tubular dysfunction may lead to increased clearance of serum lipase and potentially lower its levels.
References
1. Ko K, Tello LC, Salt J. Acute pancreatitis with normal amylase and lipase. The Medicine Forum. 2011;11 Article 4. https://jdc.jefferson.edu/tmf/vol11/iss1/4/
2. Singh A, Shrestha M. Acute pancreatitis with normal amylase and lipase-an ED dilemma. Am J Emerg Med 2016;940.e5-940.e7. https://www.ncbi.nlm.nih.gov/pubmed/26521195
3. Limon O, Sahin E, Kantar FU, et al. A rare entity in ED: normal lipase level in acute pancreatitis. Turk J Emerg Med 2016;16:32-34. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4882216/
4. Shah AM, Eddi R, Kothari ST, et al. Acute pancreatitis with normal serum lipase: a case series. J Pancreas (Online) 2010 July 5;11:369-72. PDF
5. Lott JA, Lu CJ. Lipase isoforms and amylase isoenzymes: assays and application in the diagnosis of acute pancreatitis. Clin Chem 1991;37:361-68. https://www.ncbi.nlm.nih.gov/pubmed/1706232
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Is it possible to have acute pancreatitis with normal serum lipase?

My 35 year old patient with chronic alcoholism blames benign prostatic hypertrophy for his difficulty voiding. Could his bladder dysfunction be related to his alcoholism?

Several case reports in the literature have stressed the association of bladder dysfunction (BD) with chronic alcohol abuse1,2.  Although some cases may be associated with concurrent thiamine deficiency (with its attendant neuropathy), other cases of BD do not appear to be. The mechanism of BD in this setting may be related to the toxic effect of alcohol on peripheral, autonomic and/or central nervous systems2,3.

Binge drinking may also be associated with urinary retention, with spontaneous atraumatic urinary bladder rupture having been reported on several occasions4. Lastly, alcohol withdrawal alone may precipitate urinary retention5.  

Unfortunately, many cases of abdominal pain due to urinary retention in the setting of alcohol abuse or withdrawal may be mistakenly attributed to ascites or other causes5.  High index of suspicion for BD is essential to minimize its complications.

In our patient, given the low prevalence of benign prostatic hypertrophy in men less than 40 years of age, urinary retention due to alcohol-related BD is more likely.

 

References

  1. Yuan R, Carcciolo VJ, Kulaga M. Chronic abdominal distension secondary to urinary retention in a patient with alcoholism. JAMA 2002;287;318-19.
  2. Sheremata WA, Sherwin I. Alcoholic myelopathy with spastic urinary bladder. Dis Nerv Syst 1972;33:136-139.
  3. Mellion M, Gilchrist JM, De La Monte S. Alcohol-related peripheral neuropathy: nutritional, toxic or both? Muscle Nerve 2011;43:309-16.
  4. Muneer M, Abdelrahman H, El-Menyar A, et al. Spontaneous atraumatic urinary bladder rupture secondary to alcohol intoxication: a case report and review of literature. Am J Case Rep 2015;16:778-81.
  5. Iga J-I, Taniguchi T, Ohmori T. Acute abdominal distension secondary to urinary retention in a patient after alcohol withdrawal. Alcohol Alcoholism 2005;40:86-87.
My 35 year old patient with chronic alcoholism blames benign prostatic hypertrophy for his difficulty voiding. Could his bladder dysfunction be related to his alcoholism?

My patient with chronic alcoholism is showing signs of alcohol withdrawal even though his blood alcohol level (BAL) is still elevated. Is this possible?

Absolutely! For patients with chronic alcohol dependence, any acute decline in their BAL may precipitate withdrawal (1).

For example, if a patient typically drinks enough alcohol on a daily basis to sustain a BAL of 350 mg/dl, any significant drop in BAL (e.g. down to 125 mg/dl) may be associated with early signs of withdrawal such as nervousness, tachycardia and elevated blood pressure.

Another scenario that could lead to withdrawal symptoms despite an elevated BAL involves patients who use both alcohol and benzodiazepines chronically. In such patients— because the 2 substances have cross-reactive effects on the brain— a significant reduction in the dose or frequency of benzodiazepines may also lead to withdrawal despite an elevated BAL.  Also remember that symptoms of benzodiazepine withdrawal may begin within 24 h or up to 2 weeks following its cessation (2).

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Reference

  1. Roffman JL, Stern TA.  Alcohol withdrawal in the setting of elevated blood alcohol levels. Prim Care Companion J Clin Psychiatry. 2006; 8(3):170-173 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1540391/
  2. Greenberg MI. Benzodiazepine withdrawal: potentially fatal, commonly missed, Emergency Medicine News 2001;23:18. https://journals.lww.com/em-news/pages/articleviewer.aspx?year=2001&issue=12000&article=00013&type=Fulltext

 

Contributed by Stephanie Meller, MD, Boston, MA

 

 

My patient with chronic alcoholism is showing signs of alcohol withdrawal even though his blood alcohol level (BAL) is still elevated. Is this possible?

Why is serum AST levels generally higher than ALT in alcohol-induced liver injury?

Alcohol is thought to cause injury to the mitochondria which contains AST but not ALT. In addition, in chronic alcoholics, pyridoxine (vitamin B6) deficiency may reduce the synthesis of ALT more than AST because the former is more B6-dependent (1).  

AST/ALT ratio >1 may be more common in advanced alcohol liver disease (e.g. cirrhosis) than in the setting of high alcohol consumption without severe liver disease (2). 

Also, remember that AST levels greater than 500 U/L and ALT levels greater than 300 U/L are uncommon in alcohol-related liver injury.  In this setting, other causes such as acetaminophen toxicity should be excluded (1).

Referemces

1. Johnston DE. Special considerations in interpreting liver function tests. Am Fam Physician1999;59:2223-30.  https://www.ncbi.nlm.nih.gov/pubmed/10221307  

2. Nyblom H, Berggren U, Balldin J, et al. High AST/ALT ratio may indicate advanced alcoholic liver disease rather than heavy drinking. Alcohol &Alcoholism 2004;39:336-39. https://www.ncbi.nlm.nih.gov/pubmed/15208167

Why is serum AST levels generally higher than ALT in alcohol-induced liver injury?