JW is a 51-year-old African-American male who presented with fatigue, polyuria, and polydipsia.  He had been diagnosed with insulin-dependent diabetes 1 year ago when blood tests revealed blood glucose of 625 mg/dl and hgb A1C was 18.9%.  His adherence to a diabetes treatment was poor, which led to four different hospitalizations with hyperglycemic crisis during the past year.  His family history was unknown because he was adopted. At this time his BMI is 22.2. 

Initial lab results revealed:
- Hemoglobin- 12.8 g/dl  (slightly low)
- Creatinine- 0.9 mg/dl  (average)
- Glucose- 590 mg/dl  (elevated)
- Urinary ketones- negative
- A1C-12.1%  (elevated)
- Cholesterol- 129 mg/dl  (normal)
- Triglycerides- 74 mg/dl  (normal) 
- HDL- 32 mg/dl  (low)

Subsequent lab studies reveal:
- C-peptide- 0.7 ng/ml  (slightly low)
- GAD65 antibodies- negative
- Ferritin- 1,789 ng/ml  (super elevated)
- Iron-202 ug/dl  (elevated)
- Transferrin- 276 ug/dl  (normal)
- Transferrin Sat- 73%  (elevated)
- AST- 56 U/l  (elevated)
- ALT- 76 U/l  (elevated)
- Serology- + for Hepatitis C

Questions:

1. What do the lab results suggest regarding the type of diabetes this patient has?
2. Are there further lab tests indicated to confirm any of the presented lab results? If so, what would you suggest?

While reviewing the details of this case study, the first thought that came to mind was just how uncommon it is to be diagnosed with type 1 diabetes mellitus so late in life. Typically, type 1 diabetes is diagnosed in adolescence due to symptomology that is similar to what our patient was experiencing; polyuria and polydipsia.¹

For the sake of defining these terms (mostly because admittedly, I still become confused with which one is which, as I am sure others will as well), polyuria is when a person experiences frequent urination with excessive volume, likely due to polydipsia, which is insatiable thirst due to elevated blood sugar.^2,3 Additionally, blood glucose is extremely elevated along with A1C, therefore diabetes would definitely be a viable diagnosis.

However, as we review the rest of the blood panel, it becomes apparent that our primary diagnosis may be more related to liver function and disease states, and that the type 1 diabetes diagnosis is more likely to be a secondary disease. Noting that our patient’s hemoglobin is slightly below normal range as well I would suggest further investigation into our patient’s blood iron status.  

FERRITIN: Ferritin is our primary iron storage protein and serum levels can help us see whether the body is sufficiently storing iron.⁴ However, in our patient’s situation, both his ferritin and iron levels are high. Normal range for ferritin is between 20 – 250ng/ml for adult males. Ferritin is also reflective of the amount of iron storage within the body. It is released in relation to the amount of iron in the blood. Increased ferritin could mean that more iron is being absorbed than what is needed.⁵

Elevated ferritin (hyperferritinaemia) is associated with liver disease states such as fibrosis and non-alcoholic fatty liver disease. However, it is not specific to liver injury and warrants further investigation.⁶

IRON: For an adult male, normal iron range is 80-180ug/ml.⁴ This could be indicative of a few issues and would warrant further investigation. If our patient is experiencing iron overload, the liver will store excess iron to protect other organs. Chronic iron overload could result in liver injury or damage due to increased cellular ROS. Elevated ferritin and iron levels outside of potential iron overload could also indicate liver disease, renal failure, chronic inflammation, MetS, or chronic alcohol or drug use.^7,11

TRANSFERRIN: Transferrin is a protein that transports iron in the blood, and is related to other biomarkers saturated transferrin, TIBC, and UIBC. Our patient’s transferrin seems to be within range, but saturated transferrin is elevated. Normal range for saturated transferrin is 20%-50%.⁸

Further, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are elevated as well. These are liver enzymes that also can indicate liver injury.

Potential Risk Factors:

• Hepatitis C (positive test)
• Anemia
• Hemochromatosis
• Blood transfusions, sharing of needles, unprotected sex.

We know that our patient tested positive for hepatitis C, so elevated iron biomarkers and liver enzyme levels could be expected here. A recent review suggests that chronic hepatitis C causes iron overload and that iron positively correlates with the lifecycle of the disease.¹⁶

What is the connection between liver functionality and elevated blood glucose and A1C?

Diabetes and hepatitis C have an association. Here a few standpoints:

1. Type 2 diabetes and insulin resistance are often reported with hepatitis C.⁹
2. Patients with hepatitis C are also at an increased risk for autoimmune diseases, particularly type 1 diabetes.⁹
3. Treatment for hepatitis C with interferon alpha can trigger diabetes and anemic disease states within the patient.⁹

C-peptide: C-peptide levels can help us determine whether a patient has type 1 or type 2 diabetes as it is directly associated with the amount of insulin being produced by the pancreas. C-peptide is released at the same time as insulin and in equal amounts.^8,10 If C-peptide is low or below normal range, the pancreas may not be producing insulin, which would lead us to type 1. If C-peptide is high, it indicates that the pancreas is producing insulin, but that the body may be resistant.¹⁰

Our patient is at 0.7ng/mL, which is just slightly below normal at 0.78ng/mL-1.89ng/mL.⁸

Low C-peptide can also be indicative of liver disease.¹⁰

GAD65 antibodies: Presence of these antibodies can help us determine if the diabetes state is autoimmune or adult onset. The negative status in our patient indicates that there are no antibodies present for a type 1 diabetes diagnosis.¹²

Eliminating type 1 diabetes as primary disease state

I think that elevated blood glucose and A1c is a secondary symptom to a primary disease state associated with liver functionality. Liver functionality has likely been compromised due to hepatitis C disease status. It is unknown how long our patient has had hepatitis C and how it was contracted.

Iron Status & Related Diseases

1. Hepatitis C: It is possible that our patient contracted hepatitis C from a past blood transfusion, unprotected sex, or sharing of needles due to a tattoo, piercing, or intravenous drug use. Patients who received transfusions before 1992 are at an increased risk for hepatitis C contraction.^13,14
2. Anemia: It is possible that our patient suffers from a hereditary anemic disease. Low hemoglobin is a possible indication of an anemic state, but high ferritin, elevated iron, and increased saturated transferrin differentiate it from iron deficiency anemias.⁸
3. Blood transfusions: History of blood transfusions can result in iron overload.¹³ If our patient has thalassemia, there is a chance that he has received blood transfusions previously. Iron overload can impair liver function and impair pancreas functionality, which results in diabetes symptomology.¹⁵ Further, hepatitis C could have been contracted via past blood transfusion.
4. Hemochromatosis: Hemochromatosis is the overload of iron in the body. This is due to genetic mutation and is a hereditary condition that can be diagnosed later in life.¹⁷

Further testing

Our patient suffers from hemochromatosis as a result of another disease state. I think that it would be important to get a full medical history on our patient so that we might be able to eliminate or determine what came first.

Although we don’t know his family medical history, thalassemia major presents itself shortly after birth and would call for regular blood transfusions. Thalassemia intermedia may not require regular blood transfusions and our patient could have a sideroblastic or megaloblastic anemia.¹⁵ Ordering further blood tests such as a complete blood cell count to determine RBC indices would be helpful in determining potential anemic disease status.⁸

What is our patient’s history of drug and alcohol use? Does he have protected sex or was there a time when he had unprotected sex and could have been at risk for contracting HCV sexually? Does he have any tattoos, piercings, or shared any needles? It would be important to find out this information so that we can move forward and treat the appropriate disease as well as establish prevention and nutritional recommendations to help support nutrient deficiencies that are common with liver diseases and possible anemia.

In conclusion, our patient is suffering from hepatitis C infection and hemochromatosis. It is hard to say which came first at this time but may be more apparent after running some addition blood lab work, as well as exploring individual medical history and lifestyle factors. As a result, JW is experiencing type 1 diabetes symptomology due to liver injury or damage, iron overload, and injury to the pancreas and compromising endocrine organ functionality. 

References:

1.  U.S. National Library of Medicine. Type 1 diabetes. Retrieved from https://ghr.nlm.nih.gov/condition/type-1-diabetes. Updated June 11, 2019. Accessed June 17, 2019.
2. MedlinePlus. Thirst – excessive. Retrieved from https://medlineplus.gov/ency/article/003085.htm. Accessed June 17, 2019.
3. MedlinePlus. https://medlineplus.gov/ency/article/003146.htm. Accessed June 17, 2019.
4. University of Rochester Medical Center. Ferritin (Blood). Retrieved from https://www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=167&contentid=ferritin_blood. Accessed June 18, 2019.
5. AACC. Lab Tests Online. Ferritin. Retrieved from https://labtestsonline.org/tests/ferritin. Accessed June 19, 2019.
6. Ryan DJ, Armitage AE, Cobbold JF, Banerjee R, Borsani O, et al. Hepatic iron is the major determination of serum ferritin in NAFLD patients. Liver International. 2018 Jan; 38(1):164-173.
7. Koperdanova M, Cullis JO. Interpreting raised serum ferritin levels. BMJ 2015; 351 :h3692
8. Pagana KD, Pagana TJ. Mosby’s Manual if Diagnostic and Laboratory Tests. 6^th ed. St. Louis, Missouri; Elsevier, Inc: 2018.
9. Hammerstad SS, Grock SF, Lee HJ, Hasham A, Sundaram N, Tomer Y. Diabetes and Hepatitis C: A Two-Way Association. Front Endocrinol (Lausanne). 2015;6:134.
10. MedlinePlus. C-Peptide Test. Retrieved from https://medlineplus.gov/lab-tests/c-peptide-test/. Accessed June 20, 2019.
11. Anderson ER, Shah YM. Iron homeostasis in the liver. Compr Physiol. 2013;3(1):315–330.
12. Towns R, Pietropaolo M. GAD65 autoantibodies and its role as biomarker of Type 1 diabetes and Latent Autoimmune Diabetes in Adults (LADA). Drugs Future. 2011;36(11):847.
13. Mishra AK, Tiwari A. Iron overload in Beta thalassaemia major and intermedia patients. Maedica (Buchar). 2013;8(4):328–332.
14. Centers for Disease Control & Prevention. Viral hepatitis. Retrieved from https://www.cdc.gov/hepatitis/hcv/cfaq.htm. Accessed June 21, 2019.
15. Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis. 2010;5:11.
16. Zou DM, Sun WL. Relationship between Hepatitis C Virus Infection and Iron Overload. Chin Med J (Engl). 2017;130(7):866–871.
17. American Diabetes Association. Hemochromatosis. Retrieved from http://www.diabetes.org/living-with-diabetes/complications/related-conditions/hemochromatosis.html. Accessed June 21, 2019.