Liver disease

How should I interpret high serum vitamin B12 levels in my patient with anemia?

FA Manian MD, MPH, , , , , , , Leave a comment

High serum B12 levels, aka hypercobalaminemia (HC),  is not rare among hospitalized patients with 1 study reporting “high” (813-1355 pg/ml) and “very high” (>1355 pg/ml) serum B12 levels in 13 and 7% of patients, respectively1.

Common causes include excess B12 intake, solid neoplasms (particularly, hepatocellular carcinoma and metastatic neoplastic liver disease), blood disorders (eg, myelodysplastic syndrome, CML, and acute leukemias, particularly AML3), and other liver diseases, including alcohol-related diseases as well as acute and chronic hepatitis.  Other inflammatory states and renal failure have also been reported2.  

Paradoxically, even in the presence of HC, a functional B12 deficiency may still exist. This may be related to poor B12 delivery to cells due to its high binding by transport proteins transcobalamin I and III in HC which may in turn cause a decrease in the binding of B12 to transcobalamin II, a key player in B12 transport to tissues2.  In this setting, elevated serum methylmalonic acid and homocysteine levels may be helpful.

References:

  1. Arendt JFB, Nexo E. Cobalamin related parameters and disease patterns in patients with increased serum cobalamin levels. PLoS ONE 2012;9:e45979. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045979
  2. Andres E, Serraj K, Zhu J. et al. The pathophysiology of elevated vitamin B12 in clinical practice. Q J Med 2013;106:505-515.https://www.ncbi.nlm.nih.gov/pubmed/23447660
How should I interpret high serum vitamin B12 levels in my patient with anemia?

What is the connection between cirrhosis and adrenal insufficiency (AI)?

FA Manian MD, MPH, , , , , , , , , Leave a comment

The prevalence of AI in patients with liver disease varies widely (30-60%). 1  However, there is no consensus on how to define AI in such patients, nor is the methodology for its evaluation standardized. 

A common criticism is the frequent reliance on total, not free, serum cortisol in cirrhosis which may overestimate the prevalence of AI because cortisol is bound to corticosteroid binding globulin and albumin, commonly found at lower concentrations in cirrhosis. However, even when based on measuring free cortisol, AI is found in 12%-29% of clinically stable cirrhotic patients. 1

 Secondary AI due to hypothalamic-pituitary dysfunction has also been reported in Child-Pugh class A, B, and C patients (42%, 69%, and 80%, respectively). 2

The mechanism of AI in cirrhosis is unclear, but low serum cholesterol in cirrhosis leading to lack of substrate for steroidogenesis, and increased levels of circulating endotoxin and pro-inflammatory cytokines impairing the hypothalamic-pituitary-adrenal axis have been postulated. 1

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References

  1. Fede G, Spadaro L, Purrello F. Review: adrenal insufficiency in liver disease. J Liver 2014;3:1. https://www.ncbi.nlm.nih.gov/pubmed/22234976
  2. Zietz, B, Lock, G, Plach, B, et al. Dysfunction of the hypothalamic-pituitary-glandular axes and relation to Child-Pugh classification in male patients with alcoholic and virus-related cirrhosis. Eur J Gastroenterol Hepatology 2003;15:495-501. https://www.ncbi.nlm.nih.gov/pubmed/12702906
What is the connection between cirrhosis and adrenal insufficiency (AI)?

What is the association between sepsis and jaundice in patients without biliary obstruction?

FA Manian MD, MPH, , Leave a comment

Up to 20% of cases of jaundice in community hospitals may be due to sepsis and bacterial infections, often occurring within a few days of onset of bacteremia or even before other clinical features of infection become apparent. 1 

Although biliary obstruction as the cause of jaundice is usually suspected, many patients lack extrahepatic cause for their jaundice. Gram-negative bacteria (eg, E. coli) are often the culprit with intraabdominal or urinary tract infection, pneumonia, endocarditis, and meningitis sources also often cited. Hyperbilirubinemia (often 2-10 mg/dl) is commonly associated with elevated alkaline phosphatase and mild aminotransferases elevations, and usually resolves with treatment of infection.1

Although factors such as increased bilirubin load from hemolysis, hepatocellular injury, and drugs (eg, penicillins and cephalosporins) may play a role, cholestasis—likely due to cytokines such as tumor necrosis factor (TNF)α— is the predominant cause. 1  

Interestingly, anti-TNF-α antibodies block reduction in bile flow and bile salt excretion in laboratory animals2. 

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References

  1. Chand N, Sanyal AJ. Sepsis-induced cholestasis. HEPATOLOGY 2007;45: 230-240. https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.21480
  2. Whiting J, Green R, Rosenbluth A, Gollan J. Tumor necrosis factor-alpha decreases hepatocyte bile salt uptake and mediates endotoxin-induced cholestasis. HEPATOLOGY 1995;22:1273-1278. https://www.deepdyve.com/lp/wiley/tumor-necrosis-factor-alpha-decreases-hepatocyte-bile-salt-uptake-and-J9rdeMQBpF

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

What is the association between sepsis and jaundice in patients without biliary obstruction?

Why doesn’t excessive ingestion of carrots cause yellow discoloration of the sclera?

FA Manian MD, MPH, , , , , , , Leave a comment

Great question! “Carotenoderma” refers to the yellow discoloration of the skin caused by increased serum carotenoids1.  Carotenoids are absorbed by passive diffusion from the gastrointestinal tract which are partially metabolized in the intestinal mucosa and liver to vitamin A, and then transported in the plasma into the intercellular lipids of stratum corneum of the skin which has a high affinity for carotene1,2.

The maximal accumulation of carotenoids occurs in areas with an abundance of sweat glands (eg, the palms, soles, nasolabial folds). In the absence of strateum corneum, the sclera is spared!

Of note, there are many causes of carotenoderma besides excessive ingestion of carrots.  Among foods, increased ingestion of tomatoes, tangerines, red palm oil, and squash may also be responsible1,2. 

Systemic diseases associated with increase in serum carotenoids (possibly related to decreased conversion to vitamin A, hyperlipidemia, or other factors) include hypothyroidism, diabetes mellitus, anorexia nervosa, nephrotic syndrome, and liver disease.

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References 

  1. Horev L, Ramot Y, Klapholz L. Yellow feet in a patient with breast and thyroid carcinoma, due to oral intake of turmeric. Drug Saf-Case Rep 2015;2:4.https://link.springer.com/article/10.1007/s40800-015-0006-4
  2. Maharshak N, Shapiro J, Trau H. Carotenoderma-a review of the literature. Int J Dermatol 2003;42:178-181. http://onlinelibrary.wiley.com/doi/10.1046/j.1365-4362.2003.01657.x/epdf

 

Contributed by Clara Yang, Medical Student, Harvard Medical School

 

Why doesn’t excessive ingestion of carrots cause yellow discoloration of the sclera?

How do I interpret serum ammonia levels in hospitalized patients with altered mental status?

FA Manian MD, MPH, , , , , , , , Leave a comment

The primary source of ammonia in the blood is the intestine, where bacterial break down of urea leads to ammonia which is converted back to urea by the liver before it is excreted by the kidneys and colon. Besides hepatic dysfunction and inborn errors of metabolism, portosystemic shunts, urinary diversion, parenteral nutrition, multiple myeloma, distal renal tubular acidosis, drugs (e.g. sodium valproate), and convulsive seizures may also be associated with elevated serum ammonia levels (1).

In end-stage liver disease (ESLD), elevated serum ammonia level is neither very sensitive nor specific for the presence or the degree of hepatic encephalopathy (HE). In fact, over 2/3 of patients with ESLD without encephalopathy may have elevated serum ammonia levels (2).

In contrast, in patients with acute liver failure, an elevated serum ammonia level may be of prognostic value, with arterial ammonia levels >200 ug/dL associated with cerebral herniation in such patients (2).

In patients without suspected liver disease, measuring serum ammonia levels as part of a broader workup for mental status changes is reasonable, but just as in patients with ESLD, hyperammonia-related altered mental status should remain a diagnosis of exclusion.

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References

  1. Hawkes ND, Thomas GAO, Jurewicz A, et al. Non-hepatic hyperammonaemia: an important, potentially reversible cause of encephalopathy. Postgrad Med J 2001;77:717-722. https://pmj.bmj.com/content/77/913/717.short  
  2. Elgouhari HM, O’Shea R. What is the utility of measuring the serum ammonia level in patients with altered mental status? Cleveland Clin J Med 2009;76: 252-4.https://www.ncbi.nlm.nih.gov/pubmed/19339641

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

How do I interpret serum ammonia levels in hospitalized patients with altered mental status?

Why does my patient with cirrhosis have a normal serum albumin?

FA Manian MD, MPH, Leave a comment

The finding of normal serum albumin in cirrhotic patients is not at all uncommon. In fact, in a meta-analysis involving 8 published articles, the sensitivity of serum albumin (< 3.5 g/dL) in cirrhosis was only 45% (1).

It turns out that in many patients with cirrhosis, the synthetic ability of liver with respect to albumin appears well preserved until more advanced stages of liver dysfunction develop (2).

So don’t exclude cirrhosis just because serum albumin is normal.

 

References

1. Udell JA, Wang CS, Tinmouth J et al. Does this patient with liver disease have cirrhosis? JAMA 2012;307:832-842. https://www.ncbi.nlm.nih.gov/pubmed/22357834

2. Ballmer PE, Washe D. McNurlan M, et al. Albumin synthesis rates in cirrhosis: correlation with Child-Turcotte classification. Hepatology 1993;18:292-297. https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.1840180211

Why does my patient with cirrhosis have a normal serum albumin?

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

FA Manian MD, MPH, , Leave a comment

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).

References

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?

Is there a connection between cirrhosis and elevated CK or rhabdomyolysis?

FA Manian MD, MPH, , , , , , , Leave a comment

Besides the usual causes of rhabdomyolysis such as trauma, drugs, alcohol, sepsis, etc…, cirrhotic patients may also have what some have called “hepatic myopathy”.  

One study involving 99 patients with cirrhosis and myopathy (all with elevated serum myoglobin) found “infections” as the most common cause (47%),  followed by “idiopathic” (27%) sources as well as ETOH, herbal medicine, and trauma-related causes (<10% each) (1).  Whether this is truly an entity  or just a non-causal association is unclear.

Another study reported that ~60% of rhabdomyolysis cases in cirrhosis had no apparent cause (2), with mortality among patient with cirrhosis and rhabdomyolysis significantly higher than that of controls without cirrhosis (27.5% vs 14.5%).

So perhaps we should lower our threshold for checking serum CK in our patients with cirrhosis and weakness.

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Reference

1. Lee O-J, Yoon J-H, Lee E-J, et al. Acute myopathy associated with liver cirrhosis. World J Gastroenterol 2006;12:2254-2258.  https://www.ncbi.nlm.nih.gov/pubmed/16610032 .

2. Baek JE, Park DJ, Kim HJ, et al. The clinical characteristics of rhabdomyolysis in patients with liver cirrhosis. J Clin Gastroenterol 2007;41:317-21.

 

Is there a connection between cirrhosis and elevated CK or rhabdomyolysis?

What is the connection between cirrhosis and hyperkalemia?

FA Manian MD, MPH1 Comment

Although, many of the familiar causes of hyperkalemia, including K-sparing diuretics, renal dysfunction, and adrenal insufficieny may be present in our cirrhotic patients as well, a poorly-functioning liver itself may be the culprit.

The liver, just as the muscle tissue, plays an important role in K uptake and serves as a buffer against serum K fluctuations. In a really cool experiment involving subjects given oral K supplements under controlled conditions (1), patients with cirrhosis had much greater bump in their serum K levels than normal controls despite similar weight, renal excretion of K and a significant rise in C-peptide levels. 

So even in the absence of usual risk factors, our cirrhotic patients may be more susceptible to hyperkalemia.

1. Decaux G, Soupart A, Cauchie P, et al. Potassium homeostasis in liver cirrhosis. Arch Intern Med 1988;148:547-8.

What is the connection between cirrhosis and hyperkalemia?

What is the rationale for using N-acetylcysteine (NAC) in the treatment of non-acetaminophen-related liver failure (NALF)?

FA Manian MD, MPH, , , , , Leave a comment

Although  the evidence on the effectiveness of NAC in NALF has often been inconclusive, an 2021 meta-analysis and systematic review of the role of NAC in NALF concluded that NAC significantly improves overall survival, post-transplant survival and transplant-free survival while decreasing the overall length of hospital stay (1). 

This meta-analysis included 7 studies involving 883 patients with a mean age of 21 years in the NAC group. Significantly higher overall survival (O.R. 1.8), post-transplant survival (O.R. 2.4) and transplant-free survival (O.R. 2.9) were observed in the NAC group. 

Previously, a 2009 randomized-controlled study involving adults with NALF (including many due to drug toxicity, hepatitis B virus-HBV, and autoimmune causes) had found longer transplant-free survival—not overall survival—in the treatment group, especially among those with lower grade encephalopathy, or liver failure caused by drugs or HBV (2). 

Although it’s not clear how NAC might work in the setting of of NALF, possible effect on microcirculation or 02 delivery through interference with cytokines or other mechanisms have been suggested (2,3).  An interesting 2013 article reported lower serum levels of interleukin-17 among treated patients (3)!

Bonus Pearl: Did you know that acute liver failure affects 2000-3000 persons in the U.S. each year with a mortality as high as 30%? (3)

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References

  1. Walayat S, Shaoib H, Asghar M, et al. Role of N-acetylcysteine in non-acetominophen-related acute liver failure: an updated meta-analysis and systematic review. Ann Gastroenterol 2021;34, 1-6. http://www.annalsgastro.gr/files/journals/1/earlyview/2021/ev-01-2021-04-AG_5321-0571.pdf 
  2. Bass S, Zook N. Intravenous acetylcysteine for indications other than acetaminophen overdose. Am J Health-Syst Pharm 2013;70:1496-1501. https://www.ncbi.nlm.nih.gov/pubmed/23943180
  3. Stravitz RT, Sanyal AJ, Reisch J, et al. Effects of N-acetylcysteine on cytokines in non-acetaminophen acute liver failure: potential mechanism of improvement in transplant-free survival. Liver Int. 2013;33:1324-1331. https://utsouthwestern.pure.elsevier.com/en/publications/effects-of-n-acetylcysteine-on-cytokines-in-non-acetaminophen-acu

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

What is the rationale for using N-acetylcysteine (NAC) in the treatment of non-acetaminophen-related liver failure (NALF)?