Episode 94 - Elevated Alk Phos

Episode 94: Elevated Alk Phos. 

Akhil explains what to do when the alkaline phosphatase is elevated, including labs, imaging and other studies. 

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Elevated Alk Phos. 
By Akhil Patel, MS4, American University of the Caribbean. Comments by Hector Arreaza, MD.

Serum alkaline phosphatase: When you find elevated serum alkaline phosphatase, you must consider the two most common sources: the liver and bones. Other sources to consider include the third-trimester placenta, intestine, and kidneys. To determine if the abnormal elevation of alkaline phosphatase has clinical significance, you need to consider if it is a physiological or pathological elevation first. 

Ruling out physiological concerns: Typically, you should rule out physiological causes first as they are fewer and easier to determine via patient history. This can be even quicker to determine but also sometimes bypassed if a patient’s history and labs present with more concerning etiologies of pathological elevation.

Common causes of physiological elevations in alkaline phosphatase include pregnancy, patients with blood type O and B after eating a fatty meal, and younger children. 

Pregnancy: During pregnancy women in their third trimester will have elevated serum alk phos from the placenta. 

Blood type: During digestion, alk phos is released from the intestines in patients of blood type O and B. A postprandial increase can be 1.5 to 2 times the upper limit of normal in these patients, however, there is no clinical significance. 

Children: Younger children tend to have higher alk phos due to increased bone turnover. You can find a reference range chart online for different age groups. It is possible for alk phos to be up to three times higher in infancy and adolescence reflecting the ages with the highest bone growth velocity. 

Fun fact: Alkaline Phosphatase (also known as ALP) is a natural enzyme present in raw milk. Complete pasteurization will inactivate the enzyme in milk, therefore, presence of alkaline phosphatase in milk is an indicator of failed pasteurization. This is because the most heat-stable bacteria found in milk, Mycobacterium paratuberculosis, is destroyed by temperatures lower than those required to denature ALP.

Evaluation of pathological alkaline phosphatase: 

Degree of elevation: Another consideration is the level of alk phos elevation. If alk phos is at least four times the upper limit of normal, then cholestasis is the likely cause with many specific etiologies to consider. If alk phos is not markedly elevated (four times the upper limit) then the cause is likely not as specific and many different etiologies should be considered whether hepatic or non-hepatic.  

Liver source: 

Common symptoms: Jaundice, abdominal pain, ascites, easy bruising, nausea and/or vomiting, choluria, acholia or hypocholia, unexplained weight loss, fatigue, or anasarca.

If alk phos is elevated along with liver function testing and bilirubin, it is easier to determine the liver etiology (hepatitis, cirrhosis). However, if it is an isolated elevation in alkaline phosphatase, then other sources must be considered more carefully. 

A helpful test at this point is to look at is GGT or serum 5’-Nucleotidase for elevation. Typically, these will be elevated with alk phos if it is of liver origin. If they are not increased, you should consider bone-related etiologies.

-If a hepatic cause is determined, a right upper quadrant ultrasound is the best initial test to determine intrahepatic or extrahepatic causes. This imaging will look at the hepatic parenchyma and bile ducts. Biliary dilation on ultrasound suggests an extrahepatic cause while no dilation suggests an intrahepatic cause. 

Liver source with biliary dilation: CBD is considered dilated when >6mm. 

If biliary dilation is present suggesting an extrahepatic cause, ERCP or MRCP is the next best step in visualizing the cause with choledocholithiasis being the most common cause. Other causes to consider: malignant obstruction, primary sclerosing cholangitis strictures, chronic pancreatitis causing strictures, and AIDS cholangiopathy. 

Malignant obstructions can be from the pancreas, gallbladder, ampulla of vater, bile duct, or distant metastasis. If the results of these tests are inconclusive the next best step is to consider a liver biopsy. 

Liver source without biliary dilation: Without biliary dilation on ultrasound, there is a larger pool of etiologies to consider for intrahepatic causes: drug toxicity, primary biliary cirrhosis, primary sclerosing cholangitis, viral hepatitis, cholestasis of pregnancy, and total parenteral nutrition (TPN). 

Tests: Antimitochondrial antibody (AMA) testing is a good place to start at this point which would suggest primary biliary cirrhosis (PBC) and indicate confirmation with a liver biopsy. Other tests to order at this point include hepatitis panel, EBV and CMV, and possibly pregnancy testing. If patient history and these tests are all negative, the next best step to consider is a liver biopsy if alk phos is significantly elevated more than two times the upper limit of normal. 

Summary: GGT, Liver US, Dilated? -> MRCP, ERCP, CT scan of abdomen and pelvis. Non dilated? AMA, Hepatitis panel, EBV, CMV, pregnancy test.

Fun fact: When Alkaline phosphatase is elevated you can order the test called Alkaline Phosphatase isoenzymes. You will get a result with percentages for each isoenzyme: ALPI – intestinal, ALPL – nonspecific, but mainly expressed in liver, bone, and kidney; ALPP – placental, and ALPG – germ cells.

Nonhepatic evaluation:

With an isolated alkaline phosphatase elevation and normal GGT or serum 5’-Nucleotidase, the first thing to consider is bone-related pathologies involving high bone turnover: Healing fractures, osteomalacia, Paget’s disease of bone, osteogenic sarcoma, bone metastasis, hyperparathyroidism, and hyperthyroidism. Patient history, ordering thyroid and parathyroid function testing, imaging with bone scintigraphy are all important in sorting through the differential of bone-related pathologies. 

Other extrahepatic diseases to consider that have shown elevated alkaline phosphatase include myeloid metaplasia, peritonitis, diabetes mellitus, subacute thyroiditis, uncomplicated gastric ulcer, and sepsis. Each of these has its own work up and an elevated alk phos level has little significance clinically.

Paget’s disease of bone: 

Paget disease of bone is a benign disorder that presents with focal areas of increased bone turnover in one or more skeletal sites. 

Mostly affects male older adults, but female patients can also be affected. Commonly affects the bones of the pelvis, spine, skull, and long bones. 

Pain is the most common symptom, and the presentation of the disease may depend on which bones are affected, the extent of involvement, and the presence of complications. 

Paget’s disease of bone may be asymptomatic, incidental elevated serum alkaline phosphatase levels on routine labs or abnormal imaging tests performed for other reasons can point to Paget’s disease of bone. Other common symptoms include deafness, and tight hats. 

Diagnosis is normally done by plain radiography and serum alkaline phosphatase. Radionuclide scans is used to determine the extent of disease. Treatment with nitrogen-containing bisphosphonates (zoledronic acid, risedronate, and alendronate).

Complications of the disease include arthritis, gait changes, hearing loss, nerve compression syndromes, and osteosarcoma. 

Use serum alkaline phosphatase for assessing treatment response. Early diagnosis of Paget disease of bone is key in the management and patients have a better prognosis when treatment is initiated before complications. Consult with a specialist to confirm the diagnosis and start treatment.

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Conclusion: Now we conclude our episode number 94 “Elevated Alk Phos”. Elevated Alk Phos can be normal in some circumstances, mainly in pregnancy and childhood. You can start a workup when the alk phos is persistently elevated 4 times above the upper limit of normal. The most common causes can be grouped as hepatic and non-hepatic, and the bones is the most common non-hepatic source. Even without trying, every night you go to bed being a little wiser.

This week we thank Hector Arreaza, and Akhil Patel. Audio edition: Suraj Amrutia. Thanks for listening to Rio Bravo qWeek Podcast. If you have any feedback, contact us by email at [email protected], or visit our website riobravofmrp.org/qweek. See you next week! 

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References:

Williams, J., & Nieuwsma, J. (2016). Screening for depression in adults. In J. A. Melin (Ed.), UpToDate. Retrieved February 1, 2017, from https://www.uptodate.com/contents/screening-for-depression-in-adults.

Lawrence S Friedman, MD (2020). Approach to the patient with abnormal liver biochemical and function tests. Shilpa Grover (Ed.), UpToDate. Retrieved Maye 12, 2022 from https://www.uptodate.com/contents/approach-to-the-patient-with-abnormal-liver-biochemical-and-function-tests. 

Lawrence S Friedman, MD (2020). Enzymatic measures of cholestasis (eg, alkaline phosphatase, 5'-nucleotidase, gamma-glutamyl transpeptidase). Shilpa Grover (Ed.), UpToDate. Retrieved Maye 12, 2022 from https://www.uptodate.com/contents/enzymatic-measures-of-cholestasis-eg-alkaline-phosphatase-5-nucleotidase-gamma-glutamyl-transpeptidase.